Functionalized higher diamondoids

ABSTRACT

This invention is directed to functionalized higher diamondoids having at least one functional group. Preferably these derivatives have the following Formula I:  
                 
 
     wherein D is a higher diamondoid nucleus and wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently selected from a group consisting of hydrogen and functional groups, provided that there is at least one functional group on the derivative. The functionalized higher diamondoid compounds may also be of the formula D—L—(D) n  wherein D is a higher diamondoid nucleus and L is a linking group and n is 1 or more. The functionalized higher diamondoid compouds additionally may be of the formula R 38 —D—D—R 39  wherein D is a higher diamondoid nucleus and R 38  and R 39  are substituents.

[0001] This application is a continuation-in-part of U.S. Ser. No.10/046,486 filed Jan. 16, 2002, which claimed priority to U.S. Ser. No.60/334,939 filed Dec. 4, 2001 and to U.S. Ser. No. 60/262,843 filed Jan.19, 2001. This application claims priority to U.S. Ser. No. 60/387,341filed Jul. 18, 2002. These related applications are incorporated hereinby reference.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

[0002] The present invention is directed to functionalized higherdiamondoids. These are compounds having a higher diamondoid nucleus withone or more functional groups covalently attached. The functionalizedhigher diamondoids have applications as chemical intermediates, asmaterials for construction of nano-devices for nanotechnology, aslubricants and coatings and as components of biologically reactivematerials and the like.

[0003] References

[0004] The following publications and patents are provided forbackground information and some are cited in this application assuperscript numbers:

[0005]¹ Fort, Jr., et al., Adamantane: Consequences of the DiamondoidStructure, Chem. Rev., 64:277-300 (1964).

[0006]² Capaldi, et al., Alkenyl Adamantanes, U.S. Pat. No. 3,457,318,issued Jul. 22, 1969.

[0007]³ Thompson, Polyamide Polymer of Diamino Methyl Adamantane andDicarboxylic Acid, U.S. Pat. No. 3,832,332, issued Aug. 27, 1974.

[0008]⁴ Baum, et al., Ethynyl Adamantane Derivatives and Methods ofPolymerization Thereof, U.S. Pat. No. 5,017,734, issued May 21, 1991.

[0009]⁵ Ishii, et al., Polymerizable Adamantane Derivatives and Processfor Producing Same, U.S. Pat. No. 6,235,851, issued May 22, 2001

[0010]⁶ McKervey, et al., Synthetic Approaches to Large DiamondoidHydrocarbons, Tetrahedron, 36:971-992 (1980).

[0011]⁷ Lin, et al., Natural Occurrence of Tetramantane (C22H28),Pentamantane (C26H32) and Hexamantane (C30H36) in a Deep PetroleumReservoir, Fuel, 74(10):1512-1521 (1995).

[0012]⁸ Chen, et al., Isolation of High Purity Diamondoid Fractions andComponents, U.S. Pat. No. 5,414,189, issued May 9, 1995.

[0013]⁹ Balaban et al., Systematic Classification and Nomenclature ofDiamond Hydrocarbons-I, Tetrahedron. 34, 3599-3606 (1978).

[0014]¹⁰ Gerzon et al., The Adamantyl Group in Medicinal Agents, 1.Hypoglycemic N-Arylsulfonyl-N-adamantylureas, Vol. 6, pgs. 760-763,November 1963.

[0015]¹¹ Marshall et al., Further Studies onN-Arylsulfonyl-N-alkylureas, Vol. 6, pgs. 60-63, January 1963.

[0016]¹² Marshall et al., Some N-Arylsulfonyl-N-alkylureas, Vol. 3, pgs.927-929, Jun. 1958.

[0017]¹³ Reinhardt, Biadamantane and Some of its Derivatives, Vol. 27,pgs. 3258-3261, September 1962.

[0018]¹⁴ Sasaki et al., Synthesis of Adamantane Derivatives. II.Preparation of Some Derivatives from Adamantylacetic Acid, Vol. 41, No.1, pgs. 238-240, June 1968.

[0019]¹⁵ Stetter et al, Ein Beitrag zur Frage der Reaktivitat vonBruckenkopf-Carboniumionen, Uber Verbindungen mit Urotropin-Struktur,XXVI, pgs. 550-555, 1963.

[0020]¹⁶ Hass et al, Adamantyloxycarbonyl, a New Blocking Group.Preparation of 1-Adamantyl Chloroformate, Journal of the AmericanChemical Society, 88:9, pgs. 1988-1992, May 5, 1966

[0021]¹⁷ Stetter et al, Neue Moglichkeiten der Direktsubstitution amAdamantan, Uber Verbindungen mit Urotropin-Struktur, XLIII, Chem. Ber.102, pgs. 3357-3363, 1969.

[0022]¹⁸ von H. U. Daeniker, 206. 1-Hydrazinoadamantan, HelveticaChimica Acta, Vol. 50, Fasciculus, pgs. 2008-2010, 1967

[0023]¹⁹ Stetter et al, Uber Adamantan-phosphonsaure-(1)-dichlorid, UberVerbindungen mit Urotropin-Struktur, XLIV, Chem. Ber. 102, p. 3364-3366,1969.

[0024]²⁰ Lansbury et al, Some Reactions of α-Metalated Ethers, TheJournal of Organic Chemistry, Vol. 27, No. 6, pgs. 1933-1939, Jun. 12,1962.

[0025]²¹ Stetter et al, Herstellung von Derivaten des1-Phenyl-adamantans, Uber Verbindungen mit Urotropin-Struktur, XXXI,pgs. 3488-3492, 1964.

[0026]²² Nordlander et al, Solvolysis of 1-Adamantylcarbinyl and3-Homoadamantyl Derivatives. Mechanism of the Neopentyl CationRearrangement, Journal of the American Chemical Society, 88:19, Oct. 5,1966.

[0027]²³ Sasaki et al, Substitution Reaction of 1-Bromoadamantane inDimethyl Sulfoxide: Simple Synthesis of 1-Azidoadamantane, Journal ofthe American Chemical Society, 92:24, Dec. 2, 1970.

[0028]²⁴ Chakrabarti et al, Chemistry of Adamantane. Part II. Synthesisof 1-Adamantyloxyalkylamines, Tetrahedron Letters No. 60, pgs.6249-6252, Pergamon Press, Great Britain, 1968.

[0029]²⁵ Stetter et al. Derivate des 1-Amino-adamantans, UberVerbindungen mit Urotropin-Struktur, XXIV, pgs. 2302-2304, 1962.

[0030]²⁶ Stetter et al, Zur Kenntnis der Adamantan-carbonsaure-(1), UberVerbindungen mit Urotropin-Struktur, XVII, pgs. 1161-1166, 1960.

[0031]²⁷ Makarova et al, Psychotropic Activity of Some AminoketonesBelonging to the Adamantane Group, Pharmaceutical Chemistry Journal,Vol. 34, No. 6, 2000.

[0032] All of the above publications and patents are herein incorporatedby reference in their entirety to the same extent as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference in its entirety.

BACKGROUND INFORMATION

[0033] Diamondoids are cage-shaped hydrocarbon molecules possessingrigid structures which are tiny fragments of a diamond crystal latticeas described by Fort, Jr., et al.¹ Adamantane is the smallest member ofthe diamondoid series and consists of a single cage structure of thediamond crystal lattice. Diamantane contains two adamantane subunitsface-fused to each other, triamantane three, tetramantane four, and soon. While there is only one isomeric form of adamantane, diamantane andtriamantane, there are four different isomeric tetramantanes (i.e., fourdifferent shapes containing four adamantane subunits). Two of theisomeric tetramantanes are enantiomeric. The number of possible isomersincreases rapidly with each higher member of the diamondoid series.

[0034] Among other properties, diamondoids have by far the mostthermodynamically stable structures of all possible hydrocarbons thatpossess their molecular formulas due to the fact that diamondoids havethe same internal “crystalline lattice” structure as diamonds. It iswell established that diamonds exhibit extremely high tensile strength,extremely low chemical reactivity, electrical resistivity greater thanaluminum trioxide (Al₂O₃), excellent thermal conductivity, and superboptical properties.

[0035] Adamantane, which is commercially available, has been studiedextensively. The studies have been directed to a number of areas, suchas thermodynamic stability, functionalization and properties ofadamantane-containing materials. For instance, the following patentsdescribe adamantane derivatives and adamantane-based polymers. U.S. Pat.No. 3,457,318 teaches the preparation of polymers from alkenyladamantanes;² U.S. Pat. No. 3,832,332 describes a polyamide polymerformed from alkyladamantane diamine;³ U.S. Pat. No. 5,017,734 discussesthe formation of thermally stable resins from ethynyl adamantanederivatives;⁴ and, U.S. Pat. No. 6,235,851 reports the synthesis andpolymerization of a variety of adamantane derivatives.⁵

[0036] The higher diamondoids, which include the tetramantanes,pentamantanes, etc., have received comparatively little attention. Infact, prior to the work of inventors Dahl and Carlson embodied in U.S.Patent Application Serial No. 60/262,842 filed Jan. 19, 2001 andnumerous subsequent filings, see for example:

[0037] U.S. Ser. Nos.: 10/012,333;

[0038] 10/012,334;

[0039] 10/012,335;

[0040] 10/012,336;

[0041] 10/012,337;

[0042] 10/012,545;

[0043] 10/012,546;

[0044] 10/012,547;

[0045] 10/012,704;

[0046] 10/012,709;

[0047] 10/017,821; and

[0048] 10/046,486;

[0049] all filed on Dec. 12, 2001 and U.S. Ser. No. 10/052,636 filed onJan. 17, 2002 and all incorporated herein by reference, these compoundswere nearly hypothetical with only one such compound having beensynthesized and a few others tentatively identified (but not isolated).More specifically, McKervey, et al. reported the synthesis ofanti-tetramantane in low yields using a laborious, multistep process.⁶Lin, et al. suggested the existence of tetramantane, pentamantane andhexamantane in deep petroleum reservoirs from mass spectroscopy aloneand without any attempt to isolate materials.⁷ The possible presence oftetramantane and pentamantane in pot material recovered after adistillation of a diamondoid-containing feedstock has been discussed byChen, et al.⁸

[0050] The materials discussed in the patent applications describedabove are the higher diamondoids themselves and higher diamondoidscontaining one or more alkyl substituents, all as compounds identifiedand isolated from various petroleum feedstocks. While these materialsare of great technical and commercial importance in view of theirspecial structural, physical and chemical properties, it is also to beunderstood that it could also be advantageous to chemically modify thesehydrocarbon materials so as to introduce functional groups. It is theprocess of functionalization and the novel compounds it provides that isthe subject of this invention.

SUMMARY OF THE INVENTION

[0051] This invention is directed to functionalized higher diamondoidshaving at lest one functional group. Preferably these derivatives havethe following Formula I:

[0052] wherein D is a higher diamondoid nucleus; and, R¹, R², R³, R⁴, R⁵and R⁶ are each independently selected from a group consisting ofhydrogen and covalently bonded functional groups, provided that there isat least one functional group. More preferably the functionalized higherdiamondoids contain either one or two functional groups.

[0053] In one aspect, as described in U.S. Ser. No. 10/046,486, in thefunctionalized higher diamondoids represented by Formula I, R¹, R², R³,R⁴, R⁵ and R⁶ are preferably independently selected from a group ofmoieties consisting of —H, —F, —Cl, —Br, —I, —OH, —SH, —NH₂, —NHCOCH₃,—NHCHO, —CO₂H, —CO₂R′, —COCl, —CHO, —CH₂OH, ═O, —NO₂, —CH═CH₂, —C≡CH and—C₆H₅; where R′ is alkyl (preferably ethyl) provided that R¹, R², R³,R⁴, R⁵ and R⁶ are not all hydrogen. Typically one or two of R¹-R⁶ arenonhydrogen moieties and the remaining R's are hydrogens.

[0054] Some functionalized higher diamondoids can be prepared fromhigher diamondoid in a single reaction step. These materials arereferred to herein as “primary functionalized higher diamondoids’ andinclude, for example, higher diamondoids of Formula I wherein thefunctionalizing groups are halogens, such as -bromos and -chloros,-oxides, -hydroxyls and -nitros as well as other derivatives formed inone reaction from a higher diamondoid.

[0055] In another aspect, the functionalized higher diamondoids arematerials prepared from a primary functionalized higher diamondoid byone or more subsequent reaction steps. These materials are sometimesreferred to herein as “secondary functionalized higher diamondoids.” Itwill be appreciated that in some cases one primary functionalized higherdiamondoid may be conveniently formed by conversion of another primarymaterial. For example, a poly-bromo material can be formed either bysingle step bromination or by several repeated brominations. Similarly,a hydroxyl diamondoid can be formed directly from a diamondoid in onestep or can be prepared by reaction of a bromo-diamondoid, adiamondoid-oxide or the like. Notwithstanding this, to avoid confusion,the primary materials will not be included here in the representativesecondary materials. They will, however, be depicted in various figuresshowing reactions for forming primary and secondary materials to depictboth routes to them.

[0056] The functionalized groups available for synthesis of secondaryfunctionalized higher diamondoids can be selected from a wide range ofgroups including chloro, bromo, hydroxides, etc. Thus, the followingtypes of secondary materials are merely representatives.

[0057] Representative secondary functionalized higher diamondoidfunctional groups include fluoro, iodo, thio, sulfonyl halide,sulfonates, alkyl, haloalkyl, alkoxyl, haloalkenyl, alkynyl,haloalkynyl, hydroxyalkyl, heteroaryl, alkylthio, alkoxy; aminoalkyl,aminoalkoxy, aryl, heterocycloalkoxy, cycloalkyloxy, aryloxy, andheteroaryloxy.

[0058] Other functional groups that can be present in secondaryfunctionalized higher diamondoids are represented by the formula —C(O)Zwherein Z is hydrogen, alkyl, halo, haloalkyl, halothio, amino,monosubstituted amino, disubstituted amino, cycloalkyl, aryl,heteroaryl, heterocyclic; by —CO₂Z wherein Z is as defined previously;by —R⁷COZ and —R⁷CO₂Z wherein R⁷ is alkylene, aminoalkylene, orhaloalkylene and Z is as defined previously; by —NH₂; —NHR′, —NR′R″, and—N⁺R′R″R′″ wherein R′, R″, and R′″ are independently alkyl, amino, thio,thioalkyl, heteroalkyl, aryl, or heteroaryl; by —R⁸NHCOR⁹ wherein R⁸ is—CH₂, —OCH₂, —NHCH₂, —CH₂CH₂, —OCH₂CH₂ and R⁹ is alkyl, aryl,heteroaryl, aralkyl,or heteroaralkly; and by —R¹⁰CONHR¹¹ wherein R¹⁰ isselected from —CH₂, —OCH₂, —NHCH₂, —CH₂CH₂, and —OCH₂CH₂, and R¹¹ isselected from alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.

[0059] In a further aspect, one or more of the functional groups on thefunctionalized higher diamondoids may be of the formulae:

[0060] wherein n is 2 or 3; X is —O—, —S—, or —C(O)—; Y is ═O or ═S; andR¹², R¹³, R¹⁴, and R¹⁵ are independently hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; ═N—Z″, wherein Z″ is hydrogen, amino, hydroxyl,alkyl,

[0061] cyano, cyanoalkyl, cyanoaryl, or cyanoalkylamino.

[0062] In a further embodiment, one or more of the functional groups onthe functionalized higher diamondoid is —NHR′, —NR′R″, —N⁺R′R″R′″, or—NHQ″ wherein R′, R″, and R′″ independently are hydrogen; aryl;heteroaryl with up to 7 ring members; alkyl; alkenyl; or alkynyl,wherein the alkyl, alkenyl and alkynyl residues can be branched,unbranched or cyclized and optionally substituted with halogen, aryl orheteroaryl with up to 7 ring members; or R′ and R″ together with thenitrogen atom form a heterocyclic group with up to 7 ring members. Q″ isthio, thioalkyl, amino, monosubstituted amino, disubstituted amino, ortrisubstituted amino with an appropriate counterion such as halogen,hydroxide, sulfate, nitrate, phosphate or other anion.

[0063] In still a further embodiment, the functional group on thefunctionalized higher diamondoid is —COOR¹⁶ wherein R¹⁶ is alkyl, aryl,or aralkyl; —COR¹⁷, wherein R¹⁷ is alkyl, aryl, or heteroalkyl, —NHNHO,—R¹⁸NHCOR¹⁹ wherein R¹⁸ is absent or selected from alkyl, aryl, oraralkyl, R¹⁹ is hydrogen, alkyl, —N₂, aryl, amino, or —NHR²⁰ wherein R²⁰is hydrogen, —SO₂-aryl, —SO₂-alkyl, or —SO₂-aralkyl, —CONHR²¹ whereinR²¹ is hydrogen, alkyl, and aralkyl; —CSNHR²¹ wherein R²¹ is as definedabove; and —NR²²—(CH₂)_(n)—NR²³R²⁴, wherein R²², R²³, R²⁴ areindependantly selected from hydrogen, alkyl, and aryl, and n is from 1to 20.

[0064] In an additional embodiment, the functional group on thefunctionalized higher diamondoid may be —N═C═S; —N═C═O; —R—N═C═O;—R—N═C═S; —N═S═O; or —R—N═S═O wherein R is alkyl; —PH₂; —POX₂ wherein Xis halo; —PO(OH)₂; —OSO₃H; —SO₂H; —SOX wherein X is halo; —SO₂R whereinR is alkyl; —SO₂OR wherein R is alkyl; —SONR²⁶R²⁷ wherein R²⁶ and R²⁷are independently hydrogen or alkyl; —N₃; —OC(O)Cl; or —OC(O)SCl.

[0065] In a further aspect, the functionalizing group may form acovalent bond to two or more higher diamondoids and thus serves as alinking group between the two or more diamondoids. This providesfunctionalized higher diamondoids of Formula II:

D—L—(D)_(n)  II

[0066] wherein D is a higher diamondoid nucleus and L is a linking groupand n is 1 or more such as 1 to 10 and especially 1 to 4.

[0067] In this embodiment, the linking group L may be —N═C—N—;

[0068] wherein R²⁸,R²⁹, R³⁰, R³¹, R³², R³³ are independently hydrogen oralkyl, and n and m are independently from 2 to 20;

[0069] wherein R²⁸, R²⁹, R³⁰, R³¹, R³² and R³³ are hydrogen or alkyl;R³⁴, R³⁵, R³⁶, and R³⁷ are independently absent or hydrogen or alkylwith the proviso that at least one of R³⁴, R³⁵, R³⁶, and R³⁷ is present;and n and m are independently from 2 to 20 or the like. The counterionmay any acceptable monovalent anion, for example, halogen, hydroxide,sulfate, nitrate, phosphate, and the like.

[0070] In another aspect, the present invention relates tofunctionalized higher diamondoids of Formula III:

R³⁸—D—D—R³⁹  III

[0071] wherein each D is a higher diamondoid nucleus and R³⁸ and R³⁹ aresubstituents on the higher diamondoid nucleus and are independentlyhydrogen or a functionalizing group. Preferably the material containseither 1 or 2 functional groups. Preferably R³⁸ and R³⁹ are halo; cyano;aryl; arylalkoxy; aminoalkyl; or —COOR⁴⁰ wherein R⁴⁰ is hydrogen oralkyl.

[0072] In an additional aspect, the present invention provides salts,individual isomers, and mixtures of isomers of higher diamondoidderivatives of Formulae I, II, and III.

[0073] The functionalized higher diamondoids of the present inventionare useful in a number of diverse areas, including, for instance,nanotechnology, drugs, drug carriers, pharmaceutical compositions,precursors for the synthesis of biologically active compounds,photoresist materials and/or resist compositions for far UV lithography,synthetic lubricants, heat resistant materials and solvent-resistantresins, and so on. For example, the higher diamondoid derivatives of thepresent invention have desirable lipophilic properties, which mayimprove the bioavailability of pharmaceutically active groups attachedthereto. Also for example, the higher diamondoid derivatives of thepresent invention have sizes comparable to protein fragments, which mayimprove their efficacy. Further for example, the substituted isomers ofthe higher diamondoids from a rigid structure and thus may be selectedsuch that they provide specific shape interaction with chiral biologicalmolecules. These chiral biological molecules include, for example,enzymes, receptors and the like. The higher diamondoid derivatives ofthe present invention may also be useful as chemical intermediates forthe synthesis of further functionalized higher diamondoid derivatives toform a variety of useful materials. For example, the diversity ofsubstitution positions on the higher diamondoids of the presentinvention which takes a variety of forms can find a variety ofapplications. Such materials include composite matrix resins, structuraladhesives and surface files that are used for aerospace structuralapplications. Furthermore, coating layers or molded products withexcellent optical, electrical or electronic and mechanical propertiesare produced for use in optical fibers, photoresist compositions,conduction materials, paint compositions and printing inks. In addition,higher diamondoid derivative containing materials will have high thermalstability making them suitable for use in environments requiring suchstability including for example, devices such as semiconductors,coatings for refractory troughs or other high temperature applications.

[0074] These diverse utilities give rise to aspects of this inventionrelated to the use of the derivatized products. For example, if thefunctionalizing groups are pharmaceutically active, this can lead topharmaceutically active functionalized higher diamondoid which can beused in pharmaceuticals and methods of treatment. Similarly, if thefunctionalized higher diamondoid is of a size and shape which interactswith biological molecules or groups, the functionalizing group need onlybe pharmaceutically acceptable to achieve biological usefulness.

[0075] Thus, in a further aspect, the present invention providespharmaceutical compositions containing a therapeutically effectiveamount of a pharmaceutically active functionalized higher diamondoid offormula I, II, and III.

[0076] In another aspect, the present invention provides a method oftreatment of a disease, in particular rheumatoid arthritis,osteoarthritis, psoriasis, allergic dermatitis, asthma,hyperresponsiveness of the airway, septic shock, glomeruloneplhritis,irritable bowel disease, Crohn's disease, ulcerative colitis,atherosclerosis, growth and metastases of malignant cells, myocardialischaemia, myoblastic leukaemia, diabetes, Alzheimer's disease,osteoporosis, burn injury, stroke, varicose veins, meningitis,idiopathic Parkinson's Disease, postencephalitic parkinsonism, andsymptomatic parkinsonism resulting from damage to the nervous systemcaused by carbon monoxide intoxication as well as in the treatment ofparkinsonism associated with cerebral arteriosclerosis, particularly inelderly patients, cardiac, circulatory and vascular diseases, especiallycardiac insufficiency; depression; hypertension; drug-inducedextrapyramidal reactions; bacterial infections; and viral infections,comprising administration of a therapeutically effective amount of apharmaceutically active functionalized higher diamondoid of Formulae I,II and III or its pharmaceutically acceptable salt. The presentinvention preferably provides a method of treatment of viral infections,in particular HIV, comprising administration of a therapeuticallyeffective amount of a functionalized higher diamondoid of Formulae I,II, and III or their pharmaceutically acceptable salt.

[0077] The functionalized higher diamondoids of the present inventionmay also be useful as intermediates for the synthesis of furtherfunctionalized higher diamondoids.

BRIEF DESCRIPTION OF THE DRAWINGS

[0078]FIG. 1 illustrates the cage-shaped structure of diamondoids andtheir correlation to diamonds. Specifically, illustrated is thecorrelation of the structures of diamondoids to subunits of the diamondcrystal lattice.

[0079]FIG. 2 shows the numbering of four tetramantanes and points outrepresentative secondary, tertiary and quaternary carbon atoms.

[0080]FIG. 3 is a flow chart representing the various steps used in theisolation of higher diamondoid-containing fractions and individualhigher diamondoid components which may be functionalized. Note that thesteps can in some cases be used in a different sequence and possiblyskipped as discussed in the Examples.

[0081]FIGS. 4A and 4B are compilations of the GC/MS and HPLC propertiesof various higher diamondoids employed in this invention.

[0082]FIG. 5 shows a flow chart for a strategy of functionalization ofhigher diamondoids.

[0083]FIG. 6 shows three major reactions sorted by mechanism for theformation of primary functionalized higher diamondoids and somerepresentative secondary functionalized materials which can be preparedfrom them.

[0084]FIG. 7 shows representative pathways by which higher diamondoidcarbocations are generated, wherein D is a higher diamondoid nucleus.

[0085]FIG. 8 shows representative pathways by which higher diamondoidsare functionalized via higher diamondoid carbocations (S_(N)1reactions), wherein D is a higher diamondoid nucleus.

[0086]FIG. 9 shows representative pathways by which higher diamondoidsare functionalized via electrophilic substitution reactions (S_(E)2reactions), wherein D is a higher diamondoid nucleus.

[0087]FIG. 10 shows representative pathways by which brominated higherdiamondoids are prepared, wherein D is a higher diamondoid nucleus.

[0088]FIG. 11 shows representative pathways by which chlorinated higherdiamondoids are prepared, wherein D is a higher diamondoid nucleus.

[0089]FIG. 12 shows representative pathways by which hydroxylated andketo higher diamondoids are prepared, wherein D is a higher diamondoidnucleus.

[0090]FIG. 13 shows representative pathways by which carboxylated,esterified, and carboxamide higher diamondoids are prepared togetherwith the subsequent reactions and derivatives thereof, wherein D is ahigher diamondoid nucleus.

[0091]FIG. 14 shows representative pathways by which acetaminated andaminated higher diamondoids and the amine hydrogen chloride salts areprepared, wherein D is a higher diamondoid nucleus.

[0092]FIG. 15 shows representative pathways by which nitro higherdiamondoids are prepared and their conversion to aminated higherdiamondoids, wherein D is a higher diamondoid nucleus.

[0093]FIG. 16 shows representative pathways by which alkylated,alkenylated, alkynylated, and arylated higher diamondoids are prepared,wherein D is a higher diamondoid nucleus.

[0094]FIG. 17 shows representative reactions starting from D—COOH andthe corresponding derivatives which are formed, wherein D is a higherdiamondoid nucleus.

[0095]FIG. 18 shows representative reactions starting from D—NH₂ andD—CONH₂ and the corresponding derivatives, wherein D is a higherdiamondoid nucleus.

[0096]FIG. 19 shows representative reactions starting from D—POCl₂ andthe corresponding derivatives, wherein D is a higher diamondoid nucleus.

[0097]FIG. 20 shows representative reactions starting from D—SH orD—SOCl and the corresponding derivatives, wherein D is a higherdiamondoid nucleus.

[0098]FIG. 21 illustrates the GC/MS total ion chromatogram of thefeedstock used in Example 5 prior to bromination.

[0099]FIG. 22 shows the total ion chromatogram (TIC) of the brominationproduct of Example 5 including monobrominated, dibrominated andtribrominated tetramantane products formed (characterized by molecularion 371, 447 and 527 respectively).

[0100]FIG. 23 is the mass spectrum of a monobrominated tetramantane withGC/MS retention time of 12.038 minutes. The base peak in this spectrumis the m/z 371 molecular ion.

[0101]FIG. 24 is the mass spectrum of a tribrominated tetramantane withGC/MS retention time of 17.279 minutes. The base peak in the spectrum isthe m/z 527 molecular ion.

[0102]FIG. 25 shows the total ion chromatogram (TIC) of thehydroxylation product of Example 6.

[0103]FIG. 26 is the mass spectrum of a monohydroxylated tetramantanewith GC/MS retention time of 15.329 minutes.

[0104]FIG. 27 shows the total ion chromatogram (TIC) of theacetamination product of Example 7.

[0105]FIG. 28 is the mass spectrum of a monoacetaminated tetramantanewith GC/MS retention time of 18.098 minutes.

[0106]FIG. 29 shows the total ion chromatogram (TIC) of the aminationproduct of Example 8.

[0107]FIG. 30 is the mass spectrum of a monoaminated tetramantane withGC/MS retention time of 19.107 minutes.

DETAILED DESCRIPTION OF THE INVENTION

[0108] This Detailed Description is presented in the followingsubsections:

[0109] Definitions

[0110] Higher Diamondoids and Their Recovery

[0111] Derivatization of Higher Diamondoid

[0112] Illustrative Embodiments

[0113] Utility

[0114] Definitions

[0115] As used herein, the following terms have the following meanings.

[0116] The term “diamondoid” refers to substituted and unsubstitutedcaged compounds of the adamantane series including substituted andunsubstituted adamantane, diamantane, triamantane, tetramantane,pentamantane, hexamantane, heptamantane, octamantane, nonamantane,decamantane, undecamantane, and the like and also including variousmolecular weight forms of these components and including isomers ofthese forms. Substituted diamondoids preferably comprise from 1 to 10and more preferably 1 to 4 alkyl substituents. “Diamondoids” include“lower diamondoids” and “higher diamondoids”.

[0117] The term “lower diamondoids” or “adamantane, diamantane andtriamantane” refers to any and/or all unsubstituted and substitutedderivatives of adamantane, diamantane or triamantane. The unsubstitutedlower diamondoids show no isomers and are readily synthesized,distinguishing them from the “higher diamondoids”.

[0118] The term “higher diamondoids” refers to any and/or allsubstituted and unsubstituted tetramantanes; to any and/or allsubstituted and unsubstituted pentamantanes; to any and/or allsubstituted and unsubstituted hexamantanes; to any and/or allsubstituted and unsubstituted heptamantanes; to any and/or allsubstituted and unsubstituted octamantanes; to any and/or allsubstituted and unsubstituted nonamantanes; to any and/or allsubstituted and unsubstituted decamantanes; to any and/or allsubstituted and unsubstituted undecamantanes; as well as mixtures of theabove as well as isomers and stereoisomers.

[0119] The term “functionalized higher diamondoid” refers to a higherdiamondoid which has had at least one of its hydrogens replaced by acovalently bonded-functional moiety. The portion of the higherdiamondoid present in a functionalized higher diamondoid derivative isreferred to as a “higher diamondoid nucleus.”

[0120] The term “alkyl” refers to straight and branched chain saturatedaliphatic groups typically having from 1 to 20 carbon atoms, morepreferably 1 to 6 atoms (“lower alkyls”), as well as cyclic saturatedaliphatic groups typically having from 3 to 20 carbon atoms andpreferably from 3 to 6 carbon atoms (“lower alkyls” as well). The terms“alkyl” and “lower alkyl” are exemplified by groups such as methyl,ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. An “addedalkyl” is an alkyl that has been aynthetically bonded to a higherdiamondoid nucleus

[0121] The term “substituted alkyl” refers to an alkyl group as definedabove, having from 1 to 5 substituents, and preferably 1 to 3“substituents”. As used in these definitions the term “substituents”include materials selected from the group consisting of alkyl, alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO²-aryl and —SO₂-heteroaryl. Similarly amaterial is “substituted” when it has had one or more hydrogens replacedby one or more of these substituents.

[0122] The term “alkylene” refers to a divalent (branched or unbranched)saturated hydrocarbon chain, preferably having from 1 to 20 carbonatoms, more preferably 1 to 10 carbon atoms and even more preferably 1to 6 carbon atoms. This term is exemplified by groups such as methylene(—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and —CH(CH₃)CH₂—) and the like.

[0123] The term “substituted alkylene” refers to an alkylene group, asdefined above, having from 1 to 5 substituents, and preferably 1 to 3substituents.

[0124] The term “alkaryl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein. Such alkaryl groups are exemplified by benzyl,phenethyl and the like.

[0125] The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—,cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0126] The term “substituted alkoxy” refers to the groups substitutedalkyl-O—.

[0127] The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way ofexample, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃),n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂), methylene-t-butoxy(—CH₂—O—C(CH₃)₃) and the like.

[0128] The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, byway of example, methylenethiomethoxy (—CH₂SCH₃), ethylenethiomethoxy(—CH₂CH₂SCH₃), n-propylene-iso-thiopropoxy (—CH₂CH₂CH₂SCH(CH₃)₂),methylene-t-thiobutoxy (—CH₂SC(CH₃)₃) and the like.

[0129] The term “alkenyl” refers to a monovalent unsaturated hydrocarbongroup preferably having from 2 to 20 carbon atoms, more preferably 2 to10 carbon atoms and even more preferably 2 to 6 carbon atoms and havingat least 1 and preferably from 1-6 sites of vinyl unsaturation.Preferred alkenyl groups include ethenyl (—CH═CH₂),n-propenyl(—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like.

[0130] The term “substituted alkenyl” refers to an alkenyl group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents.

[0131] The term “alkenylene” refers to a divalent of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 40carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having at least 1 and preferably from1-6 sites of vinyl unsaturation. This term is exemplified by groups suchas ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH₂CH═CH— and—C(CH₃)═CH—) and the like.

[0132] The term “substituted alkenylene” refers to an alkenylene groupas defined above having from 1 to 5 substituents, and preferably from 1to 3 substituents.

[0133] The term “alkynyl” refers to a monovalent unsaturated hydrocarbonpreferably having from 2 to 20 carbon atoms, more preferably 2 to 20carbon atoms and even more preferably 2 to 6 carbon atoms and having atleast 1 and preferably from 1-6 sites of acetylene (triple bond)unsaturation. Preferred alkynyl groups include ethynyl (—C≡CH),propargyl (—CH₂C≡CH) and the like.

[0134] The term “substituted alkynyl” refers to an alkynyl group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents.

[0135] The term “alkynylene” refers to a divalent unsaturatedhydrocarbon preferably having from 2 to 20 carbon atoms, more preferably2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms andhaving at least 1 and preferably from 1-6 sites of acetylene (triplebond) unsaturation. Preferred alkynylene groups include ethynylene(—C≡C—), propargylene (—CH₂C≡C—) and the like.

[0136] The term “substituted alkynylene” refers to an alkynylene groupas defined above having from 1 to 5 substituents, and preferably 1 to 3substituents.

[0137] The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—,substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0138] The term “acylamino” or “aminocarbonyl” refers to the group—C(O)NRR where each R is independently hydrogen, alkyl or substitutedalkyl or where both R groups are joined to form a heterocyclic group(e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryland heterocyclic are as defined herein.

[0139] The term “aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl or substituted alkyl.

[0140] The term “aminoacyloxy” or “alkoxycarbonylamino” refers to thegroup —NRC(O)OR where each R is independently hydrogen, alkyl, asubstituted alkyl.

[0141] The term “acyloxy” refers to the groups alkyl-C(O)O—, andsubstituted alkyl-C(O)O—.

[0142] The term “aryl” refers to an unsaturated aromatic carbocyclicgroup of from 6 to 20 carbon atoms having a single ring (e.g., phenyl)or multiple condensed (fused) rings (e.g., naphthyl or anthryl).Preferred aryls include phenyl, naphthyl and the like.

[0143] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with from 1to 5 substituents, preferably 1 to 3 substituents.

[0144] The term “aryloxy” refers to the group aryl-O— wherein the arylgroup is as defined above including optionally substituted aryl groupsas also defined above.

[0145] The term “arylene” refers to the divalent derived from aryl(including substituted aryl) as defined above and is exemplified by1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and thelike.

[0146] The term “amino” refers to the group —NH₂.

[0147] The term “substituted amino” refers to the group —NRR where atleast one R is independently selected from the group consisting ofalkyl, and substituted alkyl and any other R is hydrogen.

[0148] The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups“—C(O)O-alkyl”, and “—C(O)O-substituted alkyl”.

[0149] The term “heteroaryl” refers to an aromatic group of from 1 to 15carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen andsulfur within at least one ring (if there is more than one ring).

[0150] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents.

[0151] The term “heteroaryloxy” refers to the group heteroaryl-O—.

[0152] The term “heteroarylene” refers to the divalent group derivedfrom heteroaryl (including substituted heteroaryl), as defined above,and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene,1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene,2,5-pyridnylene, 2,5-indolenyl and the like.

[0153] The term “heterocycle” or “heterocyclic” refers to a monovalentsaturated or unsaturated group having a single ring or multiplecondensed rings, from 1 to 20 carbon atoms and from 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

[0154] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 5, and preferably 1 to 3 substituents.

[0155] The term “heterocyclooxy” refers to the group heterocyclic-O—.

[0156] The term “thioheterocyclooxy” refers to the groupheterocyclic-S—.

[0157] The term “thiol” refers to the group —SH.

[0158] “Heteroalkyl” means an alkyl or cycloalkyl as defined above,carrying a substituent containing a heteroatom selected from N, O, S,S(O)_(n) where n is an integer from 0 to 2. Representative substituentsinclude —NR_(a)R_(b), —OR_(a), —SR_(a), or —S(O)_(n)R_(c), wherein n isan integer from 0 to 2. R_(a) is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, optionally substitued phenyl, optionally substitutedphenylalkyl, optionally substituted heteroaryl, or —COR where R isalkyl. R_(b) is hydrogen alkyl, —S(O)₂R where R is alkyl orhydroxylalkyl, —SO₂, —NRR′ where R and R′ are independently hydrogen oralkyl, —CONR′R″ where R′ and R″ are independently selected from hydrogenor alkyl. R_(c) is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,optionally substituted phenyl, optionally substituted heteraryl, amino,monosubstituted amino, or disubstituted amino. Representative examplesinclude, but are not limited to, 2-methoxyethyl, 2-hydroxyethyl,2-aminoethyl, 2-dimethylaminoethyl, benzyloxymethyl,thiophen-2-ylthiomethyl, and the like.

[0159] “Haloalkyl” means alkyl substituted with one or more halogenatoms, preferably one to three halogen atoms, preferably fluorine orchlorine, including those substituted with different halogens. Exemplarygroups include —CH₂Cl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CH₂CCl₃, and the like.

[0160] “Hydroxy” or “hydroxyl” means a group of —OH.

[0161] “Hydroxyalkyl” means an alkyl substituted with at least one andpreferbly 1 to 6 hydroxy group(s), provided that no two hydroxy groupsare present on the same carbon atom. Representative examples include,but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, and the like.

[0162] “Alkoxyalkyl” means an alkyl substituted with at least one alkoxygroup as defined above; or a branched monovalent hydrocarbon grouphaving 3 to 40 carbon atoms, preferably 3 to 10 carbon atoms, morepreferably 3 to 6 carbon atoms, substituted with at least one alkoxygroup as defined above. These groups include, for example,-alkylene-O-alkyl and alkylene-O-substituted alkyl Representativeexamples include methoxymethyl (—CH₂OCH₃), 2-methoxyethyl (—CH₂CH₂OCH₃),2-methoxypropyl (—CH₂—CH(OCH₃)—CH₃), and the like.

[0163] “Alkylthio” or “cycloalkylthio” means a group —SR where R isalkyl or cycloalkyl respectively as defined above, e.g., methylthio,butylthio, cyclopropylthio, and the like.

[0164] “Thioalkyl” refers to alkyl group substituted with 1 to 3 thiolgroup(s) provided that there are no two thiol groups are present on thesame carbon atom where alkyl and thiol are as defined herein, such as—CH₂CH₂SH, —CH₂SH, and the like.

[0165] The term “heterocyclothio” refers to the group heterocyclo-S—.

[0166] “Monosubstituted amino” means a group —NHR where R is alkyl,acyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, andheterocyclic, e.g., methylamino (—NHCH₃), ethylamino (—NHCH₂CH₃), andthe like.

[0167] “Disubstituted amino” means a group —NRR′ where R and R′ areindependently alkyl, acyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, heteroaryl, and heterocyclic, e.g., dimethylamino (—N(CH₃)₂),methylethylamino (—N(CH₃)CH₂CH₃), and the like.

[0168] “Trisubstituted amino” means a group —N⁺RR′R″ where R R′, and R″independently alkyl, acyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, heteroaryl, and heterocyclic, e.g., trimethylamino (—N⁺(CH₃)₃),dimethylethylamino (—N⁺(CH₃)₂CH₂CH₃), and the like.

[0169] “Thioketo” refers to S═O.

[0170] “Cyano” refers to the group —CN.

[0171] “Cyanoaryl” refers to an aryl group with at least one, preferably1 to 3 cyano substitution(s), such as —C₆H₄CN, and the like.

[0172] “Cyanoalkyl” refers to an alkyl group with at least one,preferably 1 to 3 cyano substitution(s), such as —CH₂CN, and the like.

[0173] “Cyanoalkylamino” refers to —NRR′ where R is independentlyhydrogen, alkyl, and substituted alkyl; R′ is cyanoalkyl, such as—NH(CH₂CN), —NCH₃(CH₂CN), and the like.

[0174] “Nitro” refers to the group —NO₂.

[0175] “Carbonyl” means a group —C(O)—.

[0176] “Aminoalkyl” means an alkyl substituted with at least one —NRR′where R and R′ are independently selected from hydrogen, alkyl, or acyl.Representative examples include 2-aminoethyl, 2-N,N-diethylaminopropyl,2-N-acetylaminoethyl, and the like.

[0177] “Pro-drug” means any compound which releases an active parentdrug in vivo when such prodrug is administered to a mammalian subject.

[0178] A “pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable.

[0179] A “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, and thelike.

[0180] “Pharmacologically acceptable functional group” means afunctional group on a compound to be used for a pharmaceuticalcomposition or for making such a compound. These functional groups aregenerally safe, and non-toxic.

[0181] A “therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

[0182] Higher Diamondoids and Their Recovery

[0183] As shown in FIG. 1, higher diamondoids are bridged-ringcycloalkanes that have carbon-atom frameworks that can be superimposedon the diamond crystal lattice. They are the tetramers, pentamers,hexamers, heptamers, octamers, nonamers, decamers, etc. of adamantane(tricyclo[3.3.1.1^(3,7)]decane) or C₁₀H₁₆ in which various adamantaneunits are face-fused. The higher diamondoids can contain many alkylsubstituents. These compounds have extremely rigid structures and havethe highest stability of any compound with their formula. There are fourtetramantane structures; iso-tetramantane [1(2)3], anti-tetramantane[121] and two enantiomers of skew-tetramantane [123]. There are tenpentamantanes, nine have the molecular formula C₂₆H₃₂ (molecular weight344), and among these nine there are three pairs of enantiomersrepresented by: [12(1)3], [1234], [1213] with the non-enantiomericpentamantanes represented by: [12(3)4], [1(2,3)4], [1212]. There alsoexists a more strained pentamantane, [1231], represented by themolecular formula C₂₅H₃₀ (molecular weight 330). Hexamantanes and highermaterial exist with numerous different structures.

[0184]FIG. 2 shows a representative carbon-numbering scheme for the fourtetramantanes, in which the quaternary, tertiary, and secondary carbonsare highlighted. Carbon numbering schemes for the other higherdiamondoids are similar.

[0185] The higher diamondoid families contain multiple isomers(including stereoisomers) and substituted or derivatized diamondoidswill typically contain one or more chiral centers. Higher diamondoidslarger than tetramantane exist in forms with more than one molecularweight. If desired, such compounds can be isolated as pure isomers orstereoisomers (e.g., as individual enantiomers or diastereomers, or asstereoisomer-enriched mixtures). Pure stereoisomers (or enrichedmixtures) may be prepared using, for example, crystallization, opticallyactive solvents or stereo-selective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

[0186] Higher diamondoids can be recovered from readily availablefeedstocks using the following general methods and procedures. It willbe appreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with feedstocks, but suchconditions can be determined by one skilled in the art by routineoptimization procedures.

[0187] A feedstock is selected such that it comprises recoverableamounts of higher diamondoid components. Preferred feedstocks include,for example, natural gas condensates, and refinery streams having highconcentrations of diamondoids. With regard to the latter, such refinerystreams include hydrocarbonaceous streams recoverable from crackingprocesses, distillations, coking and the like. Particularly preferredfeedstocks include condensate feedstocks recovered from the NorphletFormation in the Gulf of Mexico and from the LeDuc Formation in Canada.

[0188] The general isolation processes of higher diamondoids are shownin FIG. 3.

[0189] In one embodiment, the removal of contaminants includesdistillation of the feedstock to remove non-diamondoid components aswell as lower diamondoid components and in some cases other nonselectedhigher diamondoids having boiling points less than that of the lowestboiling point higher diamondoid component selected for recovery.

[0190] Such a distillation can be operated to fractionate the feedstocksand provide several cuts in a temperature range of interest to providethe initial enrichment of the selected higher diamondoids or groups ofselected higher diamondoids. The cuts, which are enriched in one or moreselected diamondoids or a particular diamondoid component of interest,are retained and may require further purification. The following Tableillustrates representative fractionation points that may be used toenrich various higher diamondoids in overheads. In practice it may beadvantageous to make wider temperature range cuts which would oftencontain groups of higher diamondoids which could be separated togetherin subsequent separation steps. Fractionation Points Most PreferredPreferred Useful Lower Cut Higher Cut Lower Cut Higher Cut Lower CutHigher Cut Higher Diamondoid Temperature (° C.) Temperature (° C.)Temperature (° C.) Temperature (° C.) Temperature (° C.) Temperature (°C.) Tetramantanes 349 382 330 400 300 430 Pentamantanes 385 427 360 450330 490 Cyclohexamantanes 393 466 365 500 330 550 Hexamantanes 393 466365 500 330 550 Heptamantanes 432 504 395 540 350 600 Octamantanes 454527 420 560 375 610 Nonamantanes 463 549 425 590 380 650 Decamantanes472 571 435 610 390 660 Undecamantanes 499 588 455 625 400 675

[0191] It shall be understood that substituted higher diamondoids mayaccordingly shift these preferred cut-point temperatures to highertemperatures due to the addition of substituent groups. Additionaltemperature refinements will allow for higher purity cuts for thediamondoid of interest.

[0192] Other processes for the removal of lower diamondoids, unselectedhigher diamondoids, if any, and/or hydrocarbonaceous non-diamondoidcomponents include, by way of example only, size separation techniques,evaporation either under normal or reduced pressure, crystallization,chromatography, well head separators, reduced pressure and the like.Removal processes can utilize the larger sizes of the higher diamondoidsto effect separation of lower diamondoids therefrom. For example, sizeseparation techniques using membranes will allow a feedstock retained inthe membrane to selectively pass lower diamondoids across the membranebarrier provided that the pore size of the membrane barrier is selectedto differentiate between compounds having the size of higher diamondoidcomponents as compared to lower diamondoid components. The pore size ofmolecular sieves such as zeolites and the like can also be used toeffect size separation.

[0193] In a preferred embodiment, the removal process provides for atreated feedstock having a ratio of lower diamondoid components tohigher diamondoid components of no greater than 9:1; more preferably, nogreater than 2:1; and even more preferably, the ratio is no greater than1:1. Even more preferably, after removal of the lower diamondoidcomponent(s) from the feedstock, at least about 10%, more preferably atleast 50% and still more preferably at least 90% of the higherdiamondoid components are retained in the feedstock as compared to thatamount found in the feedstock prior to the removal.

[0194] When recovery of hexamantane and higher diamondoid components isdesired and when the feedstock contains non-diamondoid contaminants, thefeedstock will also be generally subjected to pyrolysis to effectremoval of at least a portion of the hydrocarbonaceous non-diamondoidcomponents from the feedstock. The pyrolysis effectively concentratesthe amount of higher diamondoids in the pyrolytically treated feedstock.

[0195] Pyrolysis is effected by heating the feedstock under vacuumconditions or in an inert atmosphere, at a temperature of at least about390° C. and, preferably, from about 400 to about 550° C., morepreferably from about 400 to about 450° C., and especially 410 to 430°C.; for a period of time to effect pyrolysis of at least a portion ofthe non-diamondoid components of the feedstock. As described in U.S.Ser. No. 60/396,991 filed Jul. 18, 2002, incorporated herein byreference, the pyrolysis can also be carried out in the presence of ahydrocracking and/or hydrotreating catalyst in the presence of addedhydrogen. The specific conditions employed are selected such thatrecoverable amounts of selected higher diamondoid components areretained in the feedstock. The selection of such conditions is wellwithin the skill of the art.

[0196] Preferably, pyrolysis is continued for a sufficient period and ata sufficiently high temperature to thermally degrade at least about 10%of the non-diamondoid components (more preferably at least about 50% andeven more preferably at least about 90%) from the pyrolytically treatedfeedstock based on the total weight of the non-diamondoid components inthe feedstock prior to pyrolysis.

[0197] It is also preferred to further purify the recovered feedstockusing one or more purification techniques such as chromatography,crystallization, thermal diffusion techniques, zone refining,progressive recrystalization, size separation and the like. In aparticularly preferred process, the recovered feedstock is firstsubjected to gravity column chromatography using silver nitrateimpregnated silica gel followed by HPLC using two different columns ofdiffering selectivities to isolate the selected diamondoids andcrystallization to provide crystals of the highly concentrated targethigher diamondoids.

[0198]FIG. 4A is a table of relative retention times for the varioushigher diamondoids in a gas chromatography system while FIG. 4B is atable of HPLC elution times for the higher diamondoids.

[0199] Derivatization of Higher Diamondoids

[0200] There are three different carbons in the higher diamondoidsskeleton: quaternary (4° or C-4), tertiary (3° or C-3), and secondary(2° or C-2) carbons. Of those different carbons, quaternary carbons areimpossible to perform any kind of reactions on. Chemical reactions canonly take place on those tertiary (3° or C-3) and secondary (2° or C-2)carbons in the higher diamondoid skeletons. It should be mentioned thatsome of the tertiary or secondary carbons are equivalent. This meansthat the derivatives substituted at those equivalent tertiary orsecondary carbons are identical.

[0201]FIG. 5 shows a flow chart for the strategy of derivatization ofhigher diamondoids and FIG. 6 shows some representative primaryderivatives of higher diamondoids and the corresponding reactions. Asshown in FIG. 6, there are, in general, three major reactions for thederivatization of higher diamondoids sorted by mechanism: nucleophilic(S_(N)1-type) and electrophilic (S_(E)2-type) substitution reactions,and free radical reaction (details for such reactions and their use withadamantane are shown, for instance in, “Recent developments in theadamantane and related polycyclic hydrocarbons” by R. C. Bingham and P.v. R. Schleryer as a chapter of the book entitled “Chemistry ofAdamantanes”, Springer-Verlag, Berlin Heidelberg New York, 1971 and in;“Reactions of adamantanes in electrophilic media” by I. K. Moiseev, N.V. Makarova, M. N. Zemtsova published in Russian Chemical Review,68(12), 1001-1020 (1999); “Cage hydrocarbons” edited by George A. Olah,John Wiley & Son, Inc., New York, 1990).

[0202] S_(N)1 reactions involve the generation of higher diamondoidcarbocations (there are several different ways to generate the higherdiamondoid carbocations, for instance, the carbocation is generated froma parent higher diamondoid, a hydroxylated higher diamondoid or ahalogenated higher diamondoid, shown in FIG. 7), which subsequentlyreact with various nucleophiles. Some representative examples are shownin FIG. 8. Such nucleophiles include, for instance, the following: water(providing hydroxylated higher diamondoids); halide ions (providinghalogenated higher diamondoids); ammonia (providing aminated higherdiamondoids); azide (providing azidylated higher diamondoids); nitriles(the Ritter reaction, providing aminated higher diamondoids afterhydrolysis); carbon monoxide (the Koch-Haaf reaction, providingcarboxylated higher diamondoids after hydrolysis); olefins (providingalkenylated higher diamondoids after deprotonation); and aromaticreagents (providing arylated higher diamondoids after deprotonation).The reaction occurs similarly to those of open chain alkyl systems, suchas t-butyl, t-cumyl and cycloalkyl systems. Since tertiary (bridgehead)carbons of higher diamondoids are considerably more reactive thansecondary carbons under S_(N)1 reaction conditions, substitution at thetertiary carbons is favored.

[0203] S_(E)2-type reactions (i.e., electrophile substitution of a C—Hbond via a five-coordinate carbocation intermediate) include, forinstance, the following reactions: hydrogen-deuterium exchange upontreatment with deuterated superacids (e.g., DF—SbF₅ or DSO₃F—SbF₅);nitration upon treatment with nitronium salts, such as NO₂ ⁺BF₄ ⁻ or NO₂⁺PF₆ ⁻ in the presence of superacids (e.g., CF₃SO₃H); halogenation upon,for instance, reaction with Cl₂+AgSbF₆; alkylation of the bridgeheadcarbons under the Friedel-Crafts conditions (i.e., S_(E)2-type σalkylation ); carboxylation under the Koch reaction conditions; and,oxygenation under S_(E)2-type σ hydroxylation conditions (e.g., hydrogenperoxide or ozone using superacid catalysis involving H₃O₂ ⁺ or HO₃ ⁺,respectively). Some representative S_(E)2-type reactions are shown inFIG. 9.

[0204] Of those S_(N)1 and S_(E)2 reactions, S_(N)1-type reactions arethe most frequently used for the derivatization of higher diamondoids.However, such reactions produce the derivatives mainly substituted atthe tertiary carbons. Substitution at the secondary carbons of higherdiamondoids is not easy in carbonium ion processes since secondarycarbons are considerably less reactive than the bridgehead positions(tertiary carbons) in ionic processes. However, reactions at thesecondary carbons are achieved by taking advantage of the lowselectivity of free radical reactions and the high ratios of 2°(secondary) to 3° (tertiary, bridgehead) hydrogens in higherdiamondoids. Thus, free radical reactions provide a method for thepreparation of a greater number of the possible isomers of a givenhigher diamondoid than might be available by ionic precesses. Thecomplex product mixtures and/or isomers which result, however, aregenerally difficult to separate. Due to the decreased symmetry ofsubstituted higher diamondoids, free radical substitution of thesesubstrates may give rise to very complex product mixtures. Therefore, inmost cases, practical and useful free radical substitutions of higherdiamondoids can use photochlorination and/or photooxidation underspecial circumstances which permit a simpler separation of the productmixture. For instance, photochlorination is particularly useful for thesynthesis of chlorinated higher diamondoids at the secondary carbons andfurther derivatizations at the secondary carbons because chlorinatedhigher diamondoids at the secondary carbons are similar in reactivity tothose derivatized at the tertiary carbons.

[0205] Photooxidation is another powerful free radical reaction for thesynthesis of hydroxylated derivatives at the secondary carbons which arefurther oxidized to keto derivatives, which can be reduced to alcoholsproviding unique hydroxylated higher diamondoid derivatives at thesecondary carbons.

[0206] Considering this significant advantage of separating the ketohigher diamondoids, a variety of higher diamondoid derivatives at thesecondary carbons are prepared starting from the keto derivatives(higher diamondoidones), such as by reducing the keto group by, forinstance, LiAlH₄, to provide the corresponding hydroxylated derivativesat the secondary carbons and further derivatizations at the secondarycarbons starting from those hydroxylated derivatives. Higherdiamondoidones can also undergo acid-catalyzed (HCl-catalyzed)condensation reaction with, for example, excess phenol or aniline in thepresence of hydrogen chloride to form 2,2-bis(4-hydroxyphenyl) higherdiamondoids or 2,2-bis(4-aminophenyl) higher diamandoids substituted atthe secondary carbons. With the development of separation technology,such as by using up-to-date HPLC technique, we may predict that morefree radical reactions might be employed for the synthesis ofderivatives of higher diamondoids.

[0207] Using those three major types of reactions for the derivatizationof higher diamondoids, a number of higher diamondoid derivatives areprepared. Representative core reactions and the derivatives arepresented as following as either very important means to activate thehigher diamondoid nuclei or very important precursors for furtherderivatizations.

[0208]FIG. 10 shows some representative pathways for the preparation ofbrominated higher diamondoid derivatives. Mono- and multi-brominatedhigher diamondoids are some of the most versatile intermediates in thederivative chemistry of higher diamondoids. These intermediates are usedin, for example, the Koch-Haaf, the Ritter, and the Friedel-Craftsalkylation/arylation reactions. Brominated higher diamondoids areprepared by two different general routes. One involves directbromination of higher diamondoids with elemental bromine in the presenceor absence of a Lewis acid (e.g. BBr₃—AlBr₃) catalyst. The otherinvolves the substitution reaction of hydroxylated higher diamondoidswith hydrobromic acid.

[0209] Direct bromination of higher diamondoids is highly selectiveresulting in substitution at the bridgehead (tertiary) carbons. Byproper choice of catalyst and conditions, one, two, three, four, or morebromines can be introduced sequentially into the molecule, all atbridgehead positions. Without a catalyst, the mono-bromo derivative isthe major product with minor amounts of higher bromination productsbeing formed. By use of suitable catalysts, however, di-, tri-, andtetra-, penta-, and higher bromide derivatives of higher diamondoids areisolated as major products in the bromination (e.g., adding catalystmixture of boron bromide and aluminum bromide with different molarratios into the bromine reaction mixture). Typically, tetrabromo orhigher bromo derivatives are synthesized at higher temperatures in asealed tube.

[0210] To prepare bromo derivatives substituted at secondary carbons,for example, the corresponding hydroxylated higher diamondoids at thesecondary carbons is treated under mild conditions with hydrobromicacid. Preferably, higher diamondoids hydroxylated at secondary carbonsare prepared by the reduction of the corresponding keto derivative asdescribed above.

[0211] Bromination reactions of higher diamondoids are usually worked upby pouring the reaction mixture onto ice or ice water and adding asuitable amount of chloroform or ethyl ether or carbon tetrachloride tothe ice mixture. Excess bromine is removed by distillation under vacuumand addition of solid sodium disulfide or sodium hydrogen sulfide. Theorganic layer is separated and the aqueous layer is extracted bychloroform or ethyl ether or carbon tetrachloride for an additional 2-3times. The organic layers are then combined and washed with aqueoussodium hydrogen carbonate and water, and finally dried.

[0212] To isolate the brominated derivatives, the solvent is removedunder vacuum. Typically, the reaction mixture is purified by subjectingit to column chromatography on either alumina or silica gel usingstandard elution conditions (e.g., eluting with light petroleum ether,n-hexane, or cyclohexane or their mixtures with ethyl ether). Separationby preparative gas chromatography (GC) or high performance liquidchromatography (HPLC) is used where normal column chromatography isdifficult and/or the reaction is performed on extremely small quantitiesof material.

[0213] Similarly to bromination reactions, higher diamondoids arechlorinated or photochlorinated to provide a variety of mono-, di-,tri-, or even higher chlorinated derivatives of the higher diamondoids.FIG. 11 shows some representative pathways for the synthesis ofchlorinated higher diamondoid derivatives, especially those chlorinatedderivatives at the secondary carbons by way of photochlorination.

[0214]FIG. 12 shows some representative pathways for the synthesis ofhydroxylated higher diamondoids. Direct hydroxylation is also effectedon higher diamondoids upon treatment with N-hydroxyphthalimide and abinary co-catalyst in acetic acid. Hydroxylation is a very important wayof activating the higher diamondoid nuclei for further derivatizations,such as the generation of higher diamondoid carbocations under acidicconditions, which undergo the S_(N)1 reaction to provide a variety ofhigher diamondoid derivatives. In addition, hydroxylated derivatives arevery important nucleophilic agents, by which a variety of higherdiamondoid derivatives are produced. For instance, the hydroxylatedderivatives are esterified under standard conditions such as reactionwith an activated acid derivative. Alkylation to prepare ethers isperformed on the hydroxylated derivatives through nucleophilicsubstitution on appropriate alkyl halides.

[0215] The above described three core derivatives (hydroxylated higherdiamondoids and halogenated especially brominated and chlorinated higherdiamondoids), in addition to the parent higher diamondoids orsubstituted higher diamondoids directly separated from the feedstocks asdescribed above, are most frequently used for further derivatizations ofhigher diamondoids, such as hydroxylated and halogenated derivatives atthe tertiary carbons are very important precursors for the generation ofhigher diamondiod carbocations, which undergo the S_(N)1 reaction toprovide a variety of higher diamondoid derivatives thanks to thetertiary nature of the bromide or chloride or alcohol and the absence ofskeletal rearrangements in the subsequent reactions. Examples are givenbelow.

[0216]FIG. 13 shows some representative pathways for the synthesis ofcarboxylated higher diamondoids, such as the Koch-Haaf reaction,starting from hydroxylated or brominated higher diamondoids. It shouldbe mentioned that for most cases, using hydroxylated precursors getbetter yields than using brominated higher diamondoids. For instance,carboxylated derivatives are obtained from the reaction of hydroxylatedderivatives with formic acid after hydrolysis. The carboxylatedderivatives are further esterified through activation (e.g., conversionto acid chloride) and subsequent exposure to an appropriate alcohol.Those esters are reduced to provide the corresponding hydroxymethylhigher diamondoids (higher diamondoid substituted methyl alcohols,D—CH₂OH). Amide formation is also performed through activation of thecarboxylated derivative and reaction with a suitable amine. Reduction ofthe higher diamondoid carboxamide with reducing agents (e.g. lithiumaluminum hydride) provides the corresponding aminomethyl higherdiamondoids (higher diamondoid substituted methylamines, D—CH₂NH₂).

[0217]FIG. 14 shows some representative pathways for the synthesis ofacylaminated higher diamondoids, such as the Ritter reaction startingfrom hydroxylated or brominated higher diamondoids. Similarly to theKoch-Haaf reaction, using hydroxylated precursors get better yields thanusing brominated higher diamondoids in most cases. Acylaminated higherdiamondoids are converted to amino derivatives after alkalinehydrolysis. Amino higher diamondoids are further converted to, withoutpurification in most cases, amino higher diamondoid hydrochloride byintroducing hydrochloride gas into the aminated derivatives solution.Amino higher diamondoids are some of very important precursors in thesynthesis of medicines. They are also prepared from the reduction ofnitrated compounds. FIG. 15 shows some representative pathways for thesynthesis of nitro higher diamondoid derivatives. Higher diamondoids arenitrated by concentrated nitric acid in the presence of glacial aceticacid under high temperature and pressure. The nitrated higherdiamondoids are reduced to provide the corresponding amino derivatives.In turn, for some cases, amino higher diamondoids are oxidized to thecorresponding nitro derivatives if necessary. The amino derivatives arealso synthesized from the brominated derivatives by heating them in thepresence of formamide and subsequently hydrolyzing the resultant amide.

[0218] Similarly to the hydroxylated compounds, amino higher diamondsare acylated or alkylated. For instance, reaction of an amino higherdiamondoid with an activated acid derivative produces the correspondingamide. Alkylation is typically performed by reacting the amine with asuitable carbonyl containing compound in the presence of a reducingagent (e.g. lithium aluminum hydride). The amino higher diamondoidsundergo condensation reactions with carbamates such as appropriatelysubstituted ethyl N-arylsulfonylcarbamates in hot toluene to provide,for instance, N-arylsulfonyl-N′-higher diamondoidylureas.

[0219]FIG. 16 presents some representative pathways for the synthesis ofalkylated, alkenylated, alkynylated and arylated higher diamondoids,such as the Friedel-Crafts reaction. Ethenylated higher diamondoidderivatives are synthesized by reacting a brominated higher diamondoidwith ethylene in the presence of AlBr₃ followed by dehydrogen bromidewith potassium hydroxide (or the like). The ethenylated compound istransformed into the corresponding epoxide under standard reactionconditions (e.g., 3-chloroperbenzoic acid). Oxidative cleavage (e.g.,ozonolysis) of the ethenylated higher diamondoid affords the relatedaldehyde. The ethynylated higher diamondoid derivatives are obtained bytreating a brominated higher diamondoid with vinyl bromide in thepresence of AlBr₃. The resultant product is dehydrogen bromide using KOHor potassium t-butoxide to provide the desired compound.

[0220] More reactions are illustrative of methods which can be used tofunctionalize higher diamondoids. For instance, fluorination of a higherdiamondoid is carried out by reacting the higher diamondoid with amixture of poly(hydrogen fluoride) and pyridine (30% Py, 70% HF) in thepresence of nitronium tetrafluoroborate. Sulfur tetrafluoride reactswith a higher diamondoid in the presence of sulfur monochloride toafford a mixture of mono-, di-, tri- and even higher fluorinated higherdiamondoids. Iodo higher diamondoids are obtained by a substitutiveiodination of chloro, bromo or hydroxyl higher diamondoids.

[0221] Reaction of the brominated derivatives with hydrochloric acid indimethylformamide (DMF) converts the compounds to the correspondinghydroxylated derivatives. Brominated or iodinated higher diamondoids areconverted to thiolated higher diamondoids by way of, for instance,reacting with thioacetic acid to form higher diamondoid thioacetatesfollowed by removal of the acetate group under basic conditions.Brominated higher diamondoids, e.g. D—Br, is heated under reflux with anexcess (10 fold) of hydroxyalkylamine, e.g. HO—CH₂CH₂—NH₂, in thepresence of a base, e.g. triethylamine, higherdiamondoidyloxyalkylamine, e.g. D—O—CH₂CH₂—NH₂, is obtained. Onacetylation of the amines with acetic anhydride and pyridine, a varietyof N-acetyl derivatives are obtained. Direct substitution reaction ofbrominated higher diamondoids, e.g. D—Br, with sodium azide in dipolaraprotic solvents, e.g. DMF, to afford the azido higher diamondoids, e.g.D—N₃.

[0222] Higher diamondoid carboxylic acid hydrazides are prepared byconversion of higher diamondoid carboxylic acid into a chloroanhydrideby thionyl chloride and condensation with isonicotinic or nicotinic acidhydrazide (FIG. 17).

[0223] Higher diamondoidones or “higher diamondoid oxides” aresynthesized by photooxidation of higher diamondoids in the presence ofperacetic acid followed by treatment with a mixture of chromicacid-sulfuric acid. Higher diamondoidones are reduced by, for instance,LiAlH₄, to higher diamondoidols hydroxylated at the secondary carbons.Higher diamondoidones also undergo acid-catalyzed (HCl-catalyzed)condensation reaction with, for example, excess phenol or aniline in thepresence of hydrogen chloride to form 2,2-bis(4-hydroxyphenyl) higherdiamondoids or 2,2-bis(4-aminophenyl) higher diamondoids.

[0224] Higher diamondoidones (e.g. D═O) are treated with RCN(R=hydrogen, alkyl, aryl, etc.) and reduced with LiAlH₄ to give thecorresponding C-2-aminomethyl-C-2-D—OH, which are heated with COCl₂ orCSCl₂ in toluene to afford the following derivatives shown in formula IV(where Z═O or S):

[0225] Higher diamondoidones react with a suitable primary amine in anappropriate solvent to form the corresponding imines. Hydrogenation ofthe imines in ethanol using Pd/C as the catalyst at about 50° C. toafford the corresponding secondary amines. Methylation of the secondaryamines following general procedures (see, for instance, H. W. Geluk andV. G. Keiser, Organic Synthesis, 53:8 (1973)) to give the correspondingtertiary amines. Quaternization of the tertiary amines by, for instance,slowly dropping CH₃I (excess) into an ethanol solution of the amine ataround 35° C. to form the corresponding quaternary amines.

[0226] C-2 derivatives of higher diamondoids, C-2 D—R′ (R′=alkyl,alkoxy, halo, OH, Ph, COOH, CH₂COOH, NHCOCH₃, CF₃COOH) are prepared bynucleophilic substitution of higher diamondoid-C-2-spiro-C-3-diazirinein solution at 0-80° C. in the presence of an acid catalyst.

[0227] N-sulfinyl higher diamondoids [D—(NSO)_(n), n=1, 2, 3, 4, . . . ]are prepared by refluxing the higher diamondoid-HCl with SOCl₂ inbenzene for about half an hour to several hours afording mono-, di,tri-, or higher N-sulfinyl higher diamondoid derivatives.

[0228] Treatment of D—Br and/or D—Cl with HCONH₂ (wt. ratio not >1:2) at<195° C. followed by hydrolysis of the formylamino higher diamondoidsD—NHCHO with <20% HCl at <110° C. affords the amino higher diamondoidhydrochloride D—NH₂HCl.

[0229] Higher diamondoid dicarboxamides are prepared by the reaction ofhigher diamondoid dicarbonyl chloride or higher diamondoid diacetylchloride with aminoalkylamines. For instance, D—(COCl)₂ [from SOCl₂ andthe corresponding dicarboxylic acid D—(COOH)₂] are treated with(CH₃)₂NCH₂CH₂CH₂NH₂ in C₅H₅N—C₆H₆ to give N,N′-bis(dimethylaminopropyl)higher diamondoid dicarboxamide.

[0230] Aminoethoxyacetylamino higher diamondoids are prepared fromchloroacetylamino higher diamondoids and HOCH₂CH₂NR′R″. Thus, forinstance, amino higher diamondoids, D—NH₂, and ClCH₂COCl in benzene, isadded to (CH₃)₂NCH₂CH₂ONa in xylene and refluxed for about 10 hours togive aminoethoxyacetylamino higher diamondoids (R′═R″═CH₃).

[0231] Ritter reaction of C-3 D—OH and HCN gives D—NH₂; the preparationof D—NHCHO from higher diamondoids and HCN; the reaction of higherdiamondoids with nitriles gives D—NHCHO and D—NH₂; the preparation ofaza higher diamondoids from nitriles and compounds containingunsaturated OH groups, and SH groups, and so on.

[0232] Hydroxylated higher diamondoids, e.g. D—OH, react with COCl₂ orCSCl₂ to afford the higher diamondoidyloxycarbonyl derivatives, e.g.D—O—C(O)Cl or D—O—C(S)Cl the former being an important blocking group inbiochemical syntheses.

[0233]FIG. 18 shows representative reactions starting from D—NH₂ andD—CONH₂ and the corresponding derivatives, wherein D is a higherdiamondoid nucleus.

[0234]FIG. 19 shows representative reactions starting from D—POCl₂ andthe corresponding derivatives, wherein D is a higher diamondoid nucleus.

[0235]FIG. 20 shows representative reactions starting from D—SH orD—SOCl and the corresponding derivatives, wherein D is a higherdiamondoid nucleus.

[0236] Illustrative Embodiments

[0237] As set forth above this invention is directed to functionalizedhigher diamondoids having at least one functional group. Preferablythese derivatives have the structure of Formula I above.

[0238] The following table (Tabe 1) provides a representative list ofhigher diamondoid derivatives that are proposed to synthesize for eitherintermediates for medicine synthesis or medicines for pharmaceuticaluse. TABLE 1 Representative higher diamondoid derivatives HIGHERDIAMONDOID SUBSTITUENT OR DERIVATIVE tetramantane - undecamantane —CH₂Brtetramantane - undecamantane —CH═CHBr tetramantane - undecamantane—C≡CBr tetramantane - undecamantane —C₆H₄Br tetramantane - undecamantaneD—D tetramantane - undecamantane Br—D—D—Br tetramantane - undecamantaneNC—D—D—CN tetramantane - undecamantane HOOC—D—D—COOH tetramantane -undecamantane CH₃OC₆H₄—D—D—C₆H₄OCH₃ tetramantane - undecamantaneH₂NCH₂—D—D—CH₂NH₂ tetramantane - undecamantane HClH₂NCH₂—D—D—CH₂NH₂HCltetramantane - undecamantane —CH₂Cl tetramantane - undecamantane—CH═CHCl tetramantane - undecamantane —C≡CCl tetramantane -undecamantane —C₆H₄Cl tetramantane - undecamantane —CH₂OH tetramantane -undecamantane —C₆H₄OH tetramantane - undecamantane —OCOCl tetramantane -undecamantane —OCSCl tetramantane - undecamantane —OCH₃ tetramantane -undecamantane —OCH₂CH₂NH₂ tetramantane - undecamantane—OCH₂C(CH₃)₂N(CH₃)₂ tetramantane - undecamantane —O(CH₂)₅NH₂tetramantane - undecamantane —O(CH₂)₅NH₂HCl tetramantane - undecamantane

tetramantane - undecamantane

tetramantane - undecamantane —OCH₂CH₂NHC(O)CH₃ tetramantane -undecamantane ═O (keto) (oxide) tetramantane - undecamantane —C≡Ntetramantane - undecamantane —CH₂CO₂H tetramantane - undecamantane—CH₂CO₂CH₃ tetramantane - undecamantane —CF₃CO₂H tetramantane -undecamantane —CONHCH₂CH₃ tetramantane - undecamantane —NHCOCH₃tetramantane - undecamantane —CH₂NH₂ tetramantane - undecamantane ═NCH₃tetramantane - undecamantane —NHCH₃ tetramantane - undecamantane—N(CH₃)₂ tetramantane - undecamantane —N⁺(CH₃)₃ I⁻ tetramantane -undecamantane —NH₂HCl tetramantane - undecamantane —CH₂NH₂HCltetramantane - undecamantane —NHNH₂ tetramantane - undecamantane —NHCON₂tetramantane - undecamantane —NHCONH₂ tetramantane - undecamantane—NHCONHSO₂-p-C₆H₄CH₃ tetramantane - undecamantane —NHCONHSO₂-p-C₆H₄C₂H₅tetramantane - undecamantane —NHCONHSO₂-p-C₆H₄-i-C₃H₇ tetramantane -undecamantane —NHCONHSO₂-p-C₆H₄SCH₃ tetramantane - undecamantane—NHCONHSO₂-p-C₆H₄COCH₃ tetramantane - undecamantane—CH₂NHCONHSO₂-p-C₆H₄C₂H₅ tetramantane - undecamantane—CH₂NHCONHSO₂-p-C₆H₄COCH₃ tetramantane - undecamantane —NHCONHDtetramantane - undecamantane —NHCSNHD tetramantane - undecamantane—NHCSNHCH₂C₆H₅ tetramantane - undecamantane —NHCONHSO₂-p-C₆H₄Cltetramantane - undecamantane —CONH₂ tetramantane - undecamantane—CH₂CONH₂ tetramantane - undecamantane —COCH₃ tetramantane -undecamantane —N═C═N—D tetramantane - undecamantane —N═C═Stetramantane - undecamantane —N═C═O tetramantane - undecamantane —N═S═Otetramantane - undecamantane —PH₂ tetramantane - undecamantane —POCl₂tetramantane - undecamantane —PO(OH)₂ tetramantane - undecamantane —SO₂Htetramantane - undecamantane —SO₂CH₃ tetramantane - undecamantane —SOCltetramantane - undecamantane —SO₂OCH₃ tetramantane - undecamantane—SON(CH₃)₂ tetramantane - undecamantane —N₃ tetramantane - undecamantane

tetramantane - undecamantane

tetramantane - undecamantane

tetramantane - undecamantane

[0239] Utility

[0240] As set forth above the functionalized higher diamondoids of thepresent invention are expected to be useful in the treatment of viralinfections, in particular HIV, as well as chemical intermediates and asmaterials of construction.

[0241] The treatment of viral disease has been approached by inhibitingadsorption or penetration of virus into the cells, inhibitingintracellular processes which lead to the synthesis of viral components,or inhibition of release of newly synthesized virus from the infectedcell. The inhibition of one or more of these steps depends on thechemistry or mode of action of the virus.

[0242] Viruses share certain common characteristics: they consist of anucleic acid genome surrounded by a protective protein shell (capsid)and the protein shell may be enclosed in an envelope, which furtherincludes a membrane. Viruses can multiply only inside living cells afterthe virus has infected the cell and the viral genome has been introducedinto the cell. Animal viruses may differ in their types of nucleic acidwhich may be double-stranded DNA, single-stranded DNA, single-strandpositive RNA, single-strand negative RNA, and double-stranded RNA.

[0243] Double-strand DNA viruses include Hepadna viruses such as thevirus causing hepatitis B (Dane particle); Poxviridae such as theviruses causing smallpox (variola), swinepox, rabbit myxoma and orf;Herpesviridae such as the viruses causing herpes simplex (HSV-1 andHSV-2), cytomegaly, viral lymphoproliferative disease, Burkitt lymphoma,nasopharyngeal carcinoma in China, infectious mononucleosis(Epstein-barr) and chickenpox (varicella-zoster); and Adenoviridae suchas adenovirus causing acute respiratory tract disease.

[0244] Single strand DNA viruses include Papoviridae which arenon-enveloped viruses causing human warts (papillomavirus) and JC viruscausing progressive multifocal leukoencephalopathy.

[0245] Positive-strand RNA viruses include Retroviridae such as theviruses causing human T-cell leukemia (HTLV-I and HTLV-II) and AcquiredImmunodeficiency Disease (AIDS) (HIV-1 and HIV-2). The HIV viruses havemany characteristics of lentiviruses.

[0246] Positive-strand RNA viruses also include Picornaviridae such asthe enteroviruses causing polio, Coxsackie virus infections andhepatitis A.

[0247] Negative-strand RNA viruses include Orthomyxoviridae such as theviruses causing influenza A, B and C; Paramyxoviridae such as theviruses causing mumps, measles, parainfluenza, and respiratory syncytialdisease (pneumovirus); and Rhabdoviridae such as the virus causingrabies.

[0248] Double-strand RNA viruses include Reoviridae such as the virusescausing certain gastroenteritis (rotavirus).

[0249] The treatment of viral disease by chemical drugs has targetedinhibition of intracellular metabolic processes which lead to thesynthesis of viral constituents or release of virus from the host cell(late); and inhibition of absorption or penetration of the virus intothe host cell or integration of the viral genome into that of the hostcell (early).

[0250] The acitivity of the higher diamondoid derivatives of the presentinvention may be assayed by measuring the ability of the higherdiamondoid derivatives to inhibit viral infections. In this regard, acytotoxicity assay may be utilized. An effective anti-viral drug must benon-toxic to cells. Any antiviral assays must first confirm the testingcandidate is not cytotoxic to the cells used in the assay. To measurethe ability of higher diamondoids to inhibit viral infections, anti-HIVassays and virus neutralization assays may be utilized. Anti-HIV assaysand virus neutralization assays are well known to those of skill in theart.

[0251] The higher diamondoid derivatives of Formulae I, II, and III canbe administered to a patient at therapeutically effective doses to treator ameliorate a condition, disorder, or disease as described herein. Atherapeutically effective dose refers to that amount of the higherdiamondoid derivative sufficient to result in amelioration of symptomsof such a condition, disorder, or disease.

[0252] Toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD₅₀ (the dose lethal to50% of the population) and the ED₅₀ (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices arepreferred. While compounds which exhibit toxic side effects may be used,care should be taken to design a delivery system which targets suchcompounds to the site of affected tissue in order to minimize potentialdamage to uninfected cells and, thereby, reduce side effects.

[0253] The data obtained from the cell culture assays and animal studiescan be used in formulating a range of dosage for use in humans. Thedosage of such compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range which includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

[0254] As defined herein, a therapeutically effective amount of thecompound (i.e., an effective dosage) ranges from about 0.001 to 100mg/kg body weight, preferably about 0.01 to 30 mg/kg body weight, morepreferably about 0.1 to 20 mg/kg body weight, and even more preferablyabout 1 to 10 mg/kg body weight.

[0255] The skilled artisan will appreciate that certain factors mayinfluence the dosage required to effectively treat a subject, includingbut not limited to the severity of the disease or condition, disorder,or disease, previous treatments, the general health and/or age of thesubject, and other diseases present. Moreover, treatment of a subjectwith a therapeutically effective amount of the compounds can include asingle treatment or, preferably, can include a series of treatments. Ina preferred example, a subject is treated with the compound in the rangeof between about 0.1 to 20 mg/kg body weight, one time per week forbetween about 1 to 10 weeks, preferably between 2 to 8 weeks, morepreferably between about 3 to 7 weeks, and even more preferably forabout 4, 5, or 6 weeks. It will also be appreciated that the effectivedosage of the compound used for treatment may increase or decrease overthe course of a particular treatment. Changes in dosage may result andbecome apparent from the results of diagnostic assays as describedherein.

[0256] Pharmaceutical compositions for use in accordance with thepresent invention may be formulated in conventional manner using one ormore physiologically acceptable carriers or excipients.

[0257] Thus, the compounds and their physiologically acceptable saltsand solvates may be formulated for administration by inhalation orinsufflation (either through the mouth or the nose) or oral, buccal,parenteral rectal or topical administration.

[0258] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium hydrogen phosphate); lubricants (e.g., magnesiumstearate, talc or silica); disintegrants (e.g., potato starch or sodiumstarch glycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The preparations may also contain buffer salts, flavoring,coloring and sweetening agents as appropriate.

[0259] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0260] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0261] For administration by inhalation, the compounds for use accordingto the present invention are conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebuliser, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

[0262] The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0263] The compounds may also be formulated in rectal compositions suchas suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0264] In certain embodiments, it may be desirable to administer thepharmaceutical compositions of the invention locally to the area in needof treatment. This may be achieved by, for example, and not by way oflimitation, local infusion during surgery, topical application, e.g., inconjunction with a wound dressing after surgery, by injection, by meansof a catheter, by means of a suppository; or by means of an implant,said implant being of a porous, non-porous, or gelatinous material,including membranes, such as sialastic membranes, or fibers. In oneembodiment, administration can be by direct injection at the site (orformer site) of a malignant tumor or neoplastic or pre-neoplastictissue.

[0265] For topical application, the compounds may be combined with acarrier so that an effective dosage is delivered, based on the desiredactivity.

[0266] In addition to the formulations described previously, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

[0267] The compositions may, if desired, be presented in a pack ordispenser device that may contain one or more unit dosage formscontaining the active ingredient. The pack may for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

EXAMPLES

[0268] Introduction

[0269] The steps used in Example 1 are shown schematically in FIG. 3.

[0270] Example 1 describes a most universal route for isolating higherdiamondoids components which can be applied to all feedstocks. Thisprocess uses HPLC (Step 7, FIG. 3) as its final isolation step.

[0271] Example 2 describes the bromination of a mixedtetramantane-alkyltetramantane feed and shows the preparation of avariety of mono- and polybromonated tetramantane derivatives andintermediates.

[0272] Example 3 describes the preparation of hydroxylated tetramantanesand alkyl tetramantanes.

[0273] Example 4 describes the preparation of acetaminated tetramantanesand alkyltetramantanes.

[0274] Example 5 describes the preparation of animated tetramantanes andalkyltetramantanes.

[0275] Example 6 describes the control of degree of functionalization ofhigher diamondoids.

[0276] Examples 7-94 describe methods that could be used to preparevarious functionalized higher diamondoids.

[0277] Example 95 describes some representative pharmaceuticalformations and testing assays.

Example 1

[0278] This Example has seven steps (see Flow Chart in FIG. 3).

[0279] Step 1. Feedstock selection

[0280] Step 2. GCMC assay development

[0281] Step 3. Feedstock atmospheric distillation

[0282] Step 4. Vacuum fractionation of atmospheric distillation residue

[0283] Step 5. Pyrolysis of isolated fractions

[0284] Step 6. Removal of aromatic and polar nondiamondoid components

[0285] Step 7. Multi-column HPLC isolation of higher diamondoids

[0286] a) First column of first selectivity to provide fractionsenriched in specific higher diamondoids.

[0287] b) Second column of different selectivity to provide isolatedhigher diamondoids.

[0288] This example is written in terms of isolating severalhexamantanes.

[0289] Step 1—Feedstock Selection

[0290] Suitable starting materials were obtained. These materialsincluded a gas condensate, Feedstock A and a gas condensate containingpetroleum components, Feedstock B.

[0291] Step 2—GC/MS Assay Development

[0292] Feedstock A was analyzed using gas chromatography/massspectrometry to confirm the presence of target higher diamondoids and toprovide gas chromatographic retention times for these materials. Thisinformation is used to track individual higher diamondoids throughsubsequent isolation procedures. FIG. 4A is a table that lists typicalGC/MS assay information for the hexamantanes (GC retention times, massspectral molecular ion (M+) and base peak). This table (FIG. 4A) alsocontains similar GC/MS assay information for other higher diamondoids aswell as HPLC retention data for these materials. While relative GCretention times are approximately constant, non-referenced GC retentionsvary with time. It is recommended that GC/MS assay values be routinelyupdated especially when GC retention time drift is detected.

[0293] Step 3—Feedstock Atmospheric Distillation

[0294] A sample of Feedstock B was distilled into a number of fractionsbased on boiling points to separate the lower boiling point components(nondiamondoids and lower diamondoids) and for further concentration andenrichment of particular higher diamondoids in various fractions. Theyields of atmospheric distillate fractions of two separate samples ofFeedstock B are shown in Table 2, below and are contrasted to simulateddistillation yields. TABLE 2 Yields of Atmospheric DistillationFractions from Two Separate Runs of Feedstock B Sim Dis Feedstock B (Run2) Cut (° F.) Est.'d Yields (Wt %) Yields (Wt %) Difference To 349 8.07.6 0.4 349 to 491 57.0 57.7 −0.7 491 to 643 31.0 30.6 0.4 643 andhigher 4.0 4.1 −0.1 Sim Dis Feedstock B (Run 1) Cut (° F.) Est.'d Yields(Wt %) Yields (Wt %) Difference To 477 63.2 59.3 3.9 477 to 515 4.8 7.3−2.5 515 to 649 28.5 31.2 −2.7 649 and higher 3.5 2.1 1.4

[0295] Step 4—Fractionation of Atmospheric Distillation Residue byVacuum Distillation

[0296] The resulting Feedstock B atmospheric residium from Step 3(comprising 2-4 weight percent of the original feedstock) was distilledinto fractions containing higher diamondoids. The feed to this hightemperature distillation process was the atmospheric 650° F.+ bottoms.Complete Feedstock B distillation reports are given in Tables 3A and 3B.Tables 4A and 4B illustrate the distillation reports for Feedstock B650° F.+ distillation bottoms. TABLE 3A Distillation Report forFeedstock B Feedstock B Column Used: Clean 9″ × 1.4″ Protruded PackedDISTILLATION RECORD NORMALIZED ACTUAL VAPOR TEMP WEIGHT VOLUME APIDENSITY WT VOL WT VOL CUT ST-END G ml @ 60° F. 60/60 @ 60° F. PCT PCTPCT PCT 1 226-349 67.0 80 38.0 0.8348 7.61 8.54 7.39 8.26 2 349-491507.7 554 22.8 0.9170 57.65 59.12 55.98 57.23 3 491-643 269.6 268 9.11.0064 30.62 28.60 29.73 27.69 COL HOLDUP 0.2 0 6.6 1.0246 0.02 0.000.02 0.00 BTMS 643+ 36.1 35 6.6 1.0246 4.09 3.74 3.98 3.62 EOR TRAPS 0.00 0.00 0.00 0.00 TOTALS 880.6 937 100.00 100.00 97.09 96.80 LOSS 26.4 312.91 3.20 FEED 907.0 968 19.5 0.9371 100.00 100.00 BACK CALCULATED APIAND DENSITY 19.1 0.9396

[0297] TABLE 3B Distillation Report for Feedstock B Feedstock B ColumnUsed: Clean 9″ × 1.4″ Protruded Packed TEMPERATURE DEGREES F. APIGRAVITIES VAPOR PRESSURE REFLUX CUT VOLUME WEIGHT OBSERVED VLT ATM EQV.POT TORR RATIO NO ml @ 60° F. G HYD RDG TEMP ° F. 60° F. 93 225.8 26250.000 3:1 START OVERHEAD 198 349.1 277 50.000 3:1 1 80 67.0 39.6 80.038.0 321 490.8 376 50.000 3:1 2 554 507.7 24.1 80.0 22.8 Cut 2 looksMilky, White crystals form in Run Down Line. Heat Lamp applied to driptube. Cool to transfer btms to smaller flask. 208 437.7 323 10.000 3:1START OVERHEAD 378 643.3 550 10.000 3:1 3 268 269.6 9.9 75.0 9.1Shutdown due to dry pot END OF RUN TRAPS 0 0.0 VOLUME DISTILLED 902COLUMN HOLDUP 0 0.2 0.0 0.0 6.6 BOTTOMS 35 36.1 7.2 72.0 6.6 RECOVERED937 880.6 FEED CHARGED 968 907.0 20.7 80.0 19.5 LOSS 31 26.4

[0298] TABLE 4A Vacuum Distillation Report for Feedstock B Feedstock B -Atmospheric distillation resid 650° F. + bottoms Column Used: Sarnia HiVac TEMPERATURE DEGREES F. API GRAVITIES VAPOR PRESSURE REFLUX CUTVOLUME WEIGHT OBSERVED VLT ATM EQV. POT TORR RATIO NO ml 60° F. G HYDRDG TEMP ° F. 60° F. 315 601.4 350 5.000 START OVERHEAD 344 636.8 3825.000 300 READING 342 644.9 389 4.000 500 READING 344 656.3 395 3.300 1639 666.4 7.8 138.0 4.1 353 680.1 411 2.500 400 READING 364 701.6 4302.100 2 646 666.9 9.4 138.0 5.6 333 736.0 419 0.400 200 READING 336751.9 432 0.300 3 330 334.3 12.4 139.0 8.3 391 799.9 468 0.500 4 173167.7 19.0 139.0 14.5 411 851.6 500 0.270 5 181 167.3 26.8 139.0 21.7460 899.8 538 0.360 6 181 167.1 27.0 139.0 21.9 484 950.3 569 0.222 7257 238.4 26.2 139.0 21.2 Shut down distillation to check pottemperature limits with customer. (Drained trap material 5.3 grams) 472935.7 576 0.222 START OVERHEAD 521 976.3 595 0.340 8 91 85.4 23.7 139.018.9 527 999.9 610 0.235 9 85 80.8 23.0 139.0 18.2 527 1025.6 624 0.13010 98 93.8 21.6 139.0 16.9 Drained remaining trap material of 16.5 grams(˜4 grams of water) MID END OF RUN TRAPS 20 17.8 (mathematically ANDcombined) VOLUME DISTILLED 2701 COLUMN HOLDUP 4 4.0 0.0 0.0 3.4 BOTTOMS593 621.8 11.0 214.0 3.4 RECOVERED 3298 3311.7 FEED CHARGED 3298 3326.318.0 234.0 8.6 LOSS −5 14.6

[0299] TABLE 4B Distillation Report for Feedstock B-btms Feedstock B -Atmospheric distillation resid 650° F. + bottoms Column Used: Sarnia HiVac VAPOR TEMP WEIGHT VOLUME API DENSITY WT VOL WT VOL CUT ST-END G ml @60° F. 60/60 60° F. PCT PCT PCT PCT  1  601-656 666.4 639 4.1 1.043520.12 19.38 20.03 19.40  2  656-702 666.9 646 5.6 1.0321 20.14 19.5920.05 19.62  3  702-752 334.3 330 8.3 1.0122 10.09 10.01 10.05 10.02  4 752-800 167.7 173 14.5 0.9692 5.06 5.25 5.04 5.25  5  800-852 167.3 18121.7 0.9236 5.05 5.49 5.03 5.50  6  852-900 167.1 181 21.9 0.9224 5.055.49 5.02 5.50  7  900-950 238.4 257 21.2 0.9267 7.25 7.79 7.17 7.80  8 950-976 85.4 91 18.9 0.9408 2.58 2.76 2.57 2.76  9  976-1000 80.8 8518.2 0.9452 2.44 2.58 2.43 2.58 10 1000-1026 93.8 98 16.9 0.9535 2.832.97 2.82 2.98 COL HOLDUP 4.0 4 3.4 1.0489 0.12 0.12 0.12 0.12 BTMS1026+ 621.8 593 3.4 1.0489 18.78 17.98 18.69 18.01 EOR TRAPS 17.8 200.54 0.61 0.54 0.61 TOTALS 3311.7 3298 100.00 100.00 99.56 100.15 LOSS14.6 −5 0.44 −0.15 FEED 3326.3 3293 8.6 1.0100 100.00 100.00 BACKCALCULATED API & 9.4 1.0039 DENSITY

[0300] TABLE 5 Elemental Composition of Feedstock B Analyses onFeedstock B 650 + F. Resid Measured Value Nitrogen 0.991 wt % Sulfur0.863 wt % Nickel 8.61 ppm Vanadium <0.2 ppm

[0301] Table 5 illustrates the partial elemental composition ofFeedstock B atmospheric distillation (650° F.) residue including some ofthe identified impurities. Table 5 displays the weight percent nitrogen,sulfur, nickel and vanadium in Feedstock B atmospheric distillationresidue. Subsequent steps remove these materials.

[0302] Step 5—Pyrolysis of Isolated Fractions

[0303] A high-temperature reactor was used to pyrolyze and degrade aportion of the nondiamondoid components in various distillationfractions obtained in Step 4 (FIG. 3) thereby enriching the diamondoidsin the residue. The pyrolysis process was conducted at 450° C. for 19.5hours. If desired, a catalyst and added hydrogen can be used to bringabout these reactions at lower temperatures.

[0304] Step 6—Removal of Aromatic and Polar Nondiamondoid Components

[0305] The pyrolysate produced in Step 5 was passed through a silica-gelgravity chromatography column (using cyclohexane elution solvent) toremove polar compounds and asphaltenes. The use of a silver nitrateimpregnated silica gel (10 weight percent AgNO₃) provides cleanerdiamondoid-containing fractions by removing the free aromatic and polarcomponents.

[0306] Step 7—Multi-Column HPLC Isolation of Higher Diamondoids

[0307] An excellent method for isolating high-purity higher diamondoidsuses two or more HPLC columns of different selectivities in succession.

[0308] The first HPLC system consisted of two Whatman M20 10/50 ODScolumns operated in series using acetone as mobile phase at 5.00 mL/min.A series of HPLC fractions were taken.

[0309] Further purification of this combined ODS HPLC fraction wasachieved using a Hypercarb stationary phase HPLC column having adifferent selectivity in the separation of various hexamantanes than theODS column discussed above.

Example 2

[0310] Bromination of Higher Diamondoid-Containing Feedstock

[0311] Bromination of a feedstock containing a mixture of higherdiamondoids was carried out. The feedstock was derived from Feedstock Bdescribed in Example 1. A sample of Feedstock B was subjected toatmospheric distillation as set forth in Example 1, Step 3. At thecompletion of the distillation, a holdup fraction was obtained byrinsing the column. The holdup was fractionated on a Whatman M40 10/50ODS preparative scale HPLC column using acetone as mobile phase.

[0312] A fraction containing all of the tetramantanes including somealkyltetramantanes and hydrocarbon impurities was obtained. Thecomposition of this fraction is shown in FIG. 21. The tetramantanes wereidentified by mass spectra and retention times.

[0313] This fraction (about 20 mg) was mixed with excess anhydrousbromine (dried with concentrated H₂SO₄) in a 10 mL round-bottom flask.While stirring, the mixture was heated in an oil bath for about 4.5hours under nitrogen, whereby the temperature was gradually raised fromroom temperature to about 100° C. The excess bromine was then removed byevaporation and the resulting brownish product was characterized byGC/MS analysis, shown in FIGS. 22-24 as follows:

[0314]FIG. 22 shows the total ion chromatogram (TIC) of the brominationproduct of Example 3 including monobrominated, dibrominated andtribrominated tetramantane products formed (characterized by molecularion 371, 447 and 527 respectively).

[0315]FIG. 23 is the mass spectrum of a monobrominated tetramantane withGC/MS retention time of 12.038 minutes. The base peak in this spectrumis the m/z 371 molecular ion.

[0316] Other mass spectra revealed monobrominated methyltetramantaneswith GC/MS retention times of 11.992 minutes and 11.644 minutes and abase peak in this spectrum is the m/z 385 molecular ion; amonobrominated dimethyltatramantane with GC/MS retention time of 12.192minutes; a dibrominated tetramantane with GC/MS retention time of 15.753minutes with a base peak of the m/z 447 molecular ion; a dibrominatedmethyltetramantane with GC/MS retention time of 15.879 minutes with thebase peak of m/z 461 molecular ion; and dibrominateddimethyltetramantanes with GC/MS retention times of 13.970 and 14.318minutes with a base peak of the m/z 475 molecular ion.

[0317]FIG. 24 is the mass spectrum of a tribrominated tetramantane withGC/MS retention time of 17.279 minutes. The base peak in the spectrum isthe m/z 527 molecular ion.

[0318] Other mass spectra showed tribrominated methyltetramantanes withGC/MS retention times of 15.250 and 16.050 minutes.

Example 3

[0319] Hydroxylation of Brominated Tetramantanes

[0320] The brominated tetramantanes of Example 2 are mixed with about 1mL of 0.67 N hydrochloric acid and 5 mL DMF. The resultant mixture isstirred at reflux temperature for about 1 hour. The mixture is thenneutralized and the solvent was evaporated. The resulting productmixture was characterized by GC/MS analysis.

[0321]FIG. 25 shows the total ion chromatogram (TIC) of thehydroxylation product of Example 3.

[0322]FIG. 26 is the mass spectrum of a monohydroxylated tetramantanewith GC/MS retention time of 15.329 minutes.

[0323] Other mass spectrum showed a monohydroxylated methyltetramantanewith GC/MS retention time of 15.281 minutes and a monohydroxylateddimethyltetramantane with GC/MS retention time of 15.925 minutes.

Example 4

[0324] Acetaminated Tetramantanes from Hydroxylated Compounds

[0325] The above prepared hydroxylated tetramantanes are dissolved inabout 3 mL acetonitrile. While stirring the mixture, about 1 mLconcentrated sulfuric acid is slowly added to the solution, whereby themixture heats up by the reaction. After the mixture has been stirred forabout 12 hours and then left standing for about another 12 hours, theorange red solution is poured into about 10 mL ice water, whereby theacetaminated higher diamondoids are separated out by filtration in highpurity. By extracting the filtrate with CH₂Cl₂, an additional smallamount of the reaction product can be obtained. The products were thencharacterized by GC/MS analysis.

[0326]FIG. 27 shows the total ion chromatogram (TIC) of theacetamination product.

[0327]FIG. 28 is the mass spectrum of a monoacetaminated tetramantanewith GC/MS retention time of 18.098 minutes.

[0328] Other monoacetaminated methyltetramantanes were present in thereaction product of this Example.

[0329] These included a monoacetaminated methyltetramantane with GC/MSretention time of 17.905 minutes and a diacetaminated tetramantane withGC/MS retention time of 21.468 minutes.

Example 5

[0330] Aminated Tetramantanes from Acetaminated Compounds

[0331] The above prepared acetaminated tetramantanes is heated to about200° C. for about 5 hours with a solution of powdered sodium hydroxide(excess) in 2 mL diethylene glycol. After it has been cooled down, thered mixture is poured into 10 mL water and extracted with CH₂Cl₂. Theextract is dried with Na₂CO₃. After filtration, the solvent wasevaporated and the residue was characterized by GC/MS analysis.

[0332]FIG. 29 shows the total ion chromatogram (TIC) of the aminationproduct of this Example.

[0333]FIG. 30 is the mass spectrum of a monoaminated tetramantane withGC/MS retention time of 19.107 minutes, while a monoaminatedmethyltetramantanes was seen with GC/MS retention time of 18.816 minutesand a monoacetaminated dimethyltetramantanes was found with GC/MSretention time of 19.918 minutes.

Example 6

[0334] Control of Degree of Functionalization of Higher Diamondoids

[0335] Higher diamondoid has two types of active carbons (secondary andtertiary carbons) on which functionalization is possible, andfurthermore, of those active carbons such as either secondary ortertiary carbon they are not all equivalent. This means, theoreticallyspeaking, there are many possible functionalized derivatives for eithermono-, di-, or higher functionalized compounds. In addition, the degreeof functionalization of higher diamondoids are variable. However, by wayof control reaction conditions or reaction mechanism (see above), it ispossible to control the degree of functionalization to prepare, forexample, the mono-, di-, or tri-functionalized derivatives as the majorproducts. This was well demonstrated by the bromination reaction asshown in FIG. 8. If the reaction was performed without catalyst and atroom temperature, the mono-brominated product dominates the brominationproduct mixture. If trace amount of BBr₃—AlBr₃ is used, thedi-brominated derivative is the major product, and with increasing thereaction temperature, reaction time, and the amount of the catalyst,tri-, and tetra-brominated derivatives become the major product. Forexample, a higher diamondoid (37 mol) is heated to 150° C. for about 22h with anhydrous bromine (0.37 mol) in a pressure vessel. Usual work-upand purification affords a pure dibrominated derivative as the majorproduct. For another example, to a stirred mixture of 1.0 mole anhydrousbromine and 0.025 mole (2.5 mL) of boron bromide is added a fewmilligrams of aluminum bromide. The reaction mixture is maintained undera blanket of nitrogen during addition of reactants to a four-neckedflask with stirrer, reflux condenser, and gas inlet. A higher diamondoid(0.1 mole) is added portionwise from a small flask attached to thefourth neck by means of Gooch crucible tubing. After refluxing for about1.5 hours, hydrogen bromide evolution is no longer evident. Excessbromine is decomposed and the product isolation is accomplished asdescribed above. After removal of the solvent, the residue isrecrystallized from methanol and n-hexane at room temperature to providea pure dibrominated compound as major product.

[0336] In addition to control the reaction parameters or mechanism tocontrol the degree of functionalization, there is another way to controlthe degree of functionalization via repeated functionalization. Forexample, when separated the mono-functionalized derivative, use it asthe starting material for further functionalization such as from mono-to di-, and from di- to tri-, from tri- to tetra-, and so on. It isunderstood that for some cases or maybe most cases, the reaction willbecome more and more difficult and this will need to adjust the reactionparameters such as increase the reaction time or temperature.

[0337] In another aspect, it is very convenient to use a primaryfunctionalized derivative with specific degree of functionalization toprepare other derivatives with the same degree of functionalization. Forexample, hydroxylated derivatives can be readily made from correspondingbrominated compounds (see Examples 14 and 15 below).

[0338] The above three ways of controlling the degree offunctionalization of higher diamondoids are just representativeexamples. Based on the nature of the reaction and the starting materialsuch as higher diamondoid, there should be other ways to control thedegree of functionalization, which is known for the skilled in the art.

Example 7

[0339] D—CH₂CH₂—Br from D—Br

[0340] A solution of a suitable monobrominated higher diamondoid D—Br(0.046 mole) in 15 mL n-hexane in a 150-mL three-necked flask equippedwith a stirrer, a gas inlet tube and a gas discharge tube with a bubblecounter is cooled to −20 to −25° C. in a cooling bath. While stirringone introduces 4.0 g powdered freshly pulverized aluminum bromide ofhigh quality, and ethylene is conducted in such a way that the gasintake can be controlled with the bubble counter. The reaction startswith a slight darkening of the color and is completed after about 1 h.The reaction solution is decanted from the catalyst into a mixture ofether and water. The ether layer is separated off, and the aqueous phaseis extracted once more with ether. The combined ether extracts arewashed with water and dilute sodium carbonate aqueous solution. Afterthey have been dried over calcium chloride, the solvent is distilledoff. Recrystallizing from methanol affords the pure higher diamondoidylethyl bromide D—CH₂CH₂—Br.

[0341] Alkylation and Dehydrogen Bromide Reaction for the Synthesis ofHigher Diamondoid Substituted Alkenyl Bromides [D-(Alkenyl-Br)_(n)]

Example 7A

[0342] D—CH═CH—Br from D—Br

[0343] Step 1: in a 150-mL two-necked flask with a stirrer and a dryingtube, a mixture of 0.069 mole of a suitable monobromonated higherdiamondoid D—Br and 20 mL vinyl bromide is cooled to −65° C. in acooling bath. While stirring, 4.5 g powdered aluminum bromide is addedin portions and the mixture is stirred for an additional about 3 hoursat the same temperature. Then the reaction mixture is poured into amixture of 30 mL water and 30 mL ethyl ether. After vigorously stirring,the ether layer is separated and the aqueous layer is extracted oncemore with ether. The combined ether extracts are washed with water anddilute sodium carbonate solution. After it has been dried with calciumchloride and the solvent has been distilled off, the residue isdistilled under vacuum.

[0344] Step 2: a solution of 0.7 g fine powdered potassium hydroxide andthe above compound (0.012 mole) in 10 mL diethylene glycol is heated to220° C. in the oil bath for 6 hours. After cooling down the mixture isdiluted with 30 mL water and exacted with ethyl ether. The ether extractis washed twice with water and dried over calcium chloride. The residueleft behind after the ether has been distilled off is sublimated invacuum, and if necessary, the compound can be recrystallized frommethanol.

[0345] Alkylation and Dehydrogen Bromide Reaction for the Synthesis ofHigher Diamondoid Substituted Alkynyl Bromides [D-(Alkynyl-Br)_(n)]

Example 8

[0346] D—C≡C—Br from D—Br

[0347] Step 1: in a 150-mL two-necked flask with a stirrer and a dryingtube, a mixture of 0.069 mole of a suitable monobromonated higherdiamondoid D—Br and CH₂═CBr₂ (excess) is cooled to −65° C. in a coolingbath. While stirring, 4.5 g powdered aluminum bromide is added inportions and the mixture is stirred for an additional about 3 hours atthe same temperature. Then the reaction mixture is poured into a mixtureof 30 mL water and 30 mL ethyl ether. After vigorously stirring, theether layer is separated and the aqueous layer is extracted once morewith ether. The combined ether extracts are washed with water and dilutesodium carbonate solution. After it has been dried with calcium chlorideand the solvent has been distilled off, the residue is distilled undervacuum.

[0348] Step 2: 15 g powdered potassium hydroxide in 30 mL diethyleneglycol is heated to reflux with 0.046 mole of the above product forabout 9 hours in the oil bath. Compound formed is then sublimated in thecondenser and must be returned to the reaction mixture from time totime. At the end of the reaction time, the reaction mixture is distilleduntil no more solid particles go over. The distillate is extracted withethyl ether and the ether phase is washed with water and dried overcalcium chloride. A short time after the ether has been distilled off,the residue solidifies. It is sublimated under vacuum and, if necessary,recrystallized from methanol.

[0349] Arylation Reaction for the Synthesis of Higher DiamondoidSubstituted Aryl Bromides [D-(Aryl-Br)_(n)]

Example 9

[0350] D—C₆H₄—Br from D—Br

[0351] 1.1 g sublimated iron(III) chloride and high-pure C₆H₅Br (excess)are placed in a 150-mL three-necked flask, which is equipped with astirrer, a reflux condenser and a dropping funnel. While stirring andheating in the steam bath, a suitable monobrominated higher diamondoidD—Br (0.018 mole) is slowly added to the above flask over about 30minutes. The reaction mixture is heated for about an additional 3 hoursuntil the production of hydrogen bromide drops off. The mixture is keptstanding over night and poured onto a mixture of ice and hydrochloricacid. The organic phase is separated out and the aqueous solution isextracted twice with benzene. The combined benzene extracts are washedseveral times with water and dried with calcium chloride. The residuesolidifies upon cooling and is completely free of the solvent in vacuum.Recrystallization from a small amount of methanol while cooling withCO₂/trichloroethylene and further sublimation under vacuum afford a pureproduct.

[0352] Synthesis of Higher Diamondoidyl Chlorides [D—(Cl)_(n)] andHigher Diamondoid Substituted Alkyl, Alkenyl, Alkynyl or Aryl Chlorides[D-(Alkyl-Cl)_(n), D-(Alkenyl-Cl)_(n), D-(Alkynyl-Cl)_(n), orD-(Aryl-Cl)_(n)] (n=1, 2, 3, 4, . . . )

[0353] Similarly to higher diamondoid substituted alkyl, alkenyl,alkynyl, or aryl bromides, higher diamondoid substituted alkyl, alkenyl,alkynyl or aryl chlorides [D-(Alkyl-Cl)_(n), D-(Alkenyl-Cl)_(n),D-(Alkynyl-Cl)_(n), or D-(Aryl-Cl)_(n)] (n=1, 2, 3, 4, . . . ) can beprepared accordingly.

[0354] Via Chlorination Reaction of Higher Diamondoids

Example 10

[0355] Monochlorination of Higher Diamondoids

[0356] A solution of 0.074 mole of a higher diamondoid and 10 mL (8.5 g,0.092 mole) of tert-butyl chloride in 40 mL of anhydrous cyclohexane isprepared in a 0.1 L, three-necked, round-bottom flask fitted with athermometer, a stirrer, and a gas exhaust tube leading to a bubblersubmerged in water. The catalyst, aluminum chloride (total 0.46 g, 0.006mole) is added in batches of 0.05 g at regular intervals over a periodof about 8 hours. Progress of the reaction is followed conveniently bythe rate of escaping isobutane gas. Upon completion of the reaction, 10mL of 1.0 N hydrochloride acid solution is added with vigorous stirring,followed by 50 mL of ethyl ether. The organic layer is separated, washedwith 10 mL of cold water and 10 mL of a 5% sodium bicarbonate solution,and dried over anhydrous calcium chloride. After removal of the solventsunder reduced pressure, the crude product is obtained. GC analysis ofthis material reveals a composition of mainly monochlorinated higherdiamondoid with a small amount of unreacted higher diamondoid. Ifnecessary, recrystallization of a sample of this material from ethanolat −50° C. affords a pure monochlorinated higher diamondoid.

[0357] Via Photochlorination Reaction of Higher Diamondoids

Example 11

[0358] Monophotochlorination of Higher Diamondoids

[0359] Photochlorination of a higher diamondoid is carried out at roomtemperature (25-30° C.) by metering 0.037 mole of chlorine into asolution of 0.074 mole of a higher diamondoid in 100 mL of solvent inthe presence of illumination by a 150-watt ultraviolet (UV) lamp. Thesolvents employed can be carbon tetrachloride, benzene, or carbondisulfide. After a short induction period (approximately 2 minutes) thereaction may be initiated as evidenced by the fading of the chlorinecolor and the evolution of hydrogen chloride. The reaction mixture iswashed by 5% sodium carbonate aqueous solution, water, and dried overanhydrous sodium sulfate. The product obtained by concentration of thedried solution is shown by GC to consist of several mono-chlorinatedhigher diamondoid isomers. Separation of those isomers is achieved byHPLC or even normal column chromatography on alumina or silicon gel orsimply by recrystallization from methanol and sublimation under vacuumor their combination to achieve the isomer separation.

[0360] Synthesis of Hydroxylated Higher Diamondoids (HigherDiamondoidols, D—(OH)_(n)) and Higher Diamondoid Substituted Alcohols(e.g. D-(Alkyl-OH)_(n))(n=1, 2, 3, 4, . . . )

[0361] Via Direct Oxidation or Hydroxylation Reaction of HigherDiamondoids

Example 12

[0362] Monohydroxylation of Higher Diamondoids

[0363] A solution of 11.0 mmol of a higher diamondoid in 18.7 g ofmethylene chloride is mixed with 4.22 g of a solution of 1.03 g (13.5mmol) of peracetic acid in ethyl acetate. While being stirredvigorously, the solution is irradiated with a 100-watt UV light placedin an immersion well in the center of the solution. Gas evolution isevident from the start. The temperature is maintained at 40-45° C. foran about 21-hour irradiation period. At the end of this time, about 95%of the peracid had been consumed. The solution is concentrated to neardryness, treated twice in succession with 100-mL portions of toluene andreevaporated to dryness. Final drying in a desiccator affords a whitesolid. A portion of the above material is dissolved in a minimum amountof benzene-light petroleum ether. This solution is then subjected tochromatography on alumina in the usual manner eluting with firstly 1:1benzene/light petroleum ether, followed by a mixture of methanol andethyl ether to collect the unreacted higher diamondoid, and thehydroxylated higher diamondoid isomers, respectively. Further separationof the isomers can be achieved by using HPLC technique.

[0364] Alternatively, to a 25 mL of acetic acid are added 10 mmol of ahigher diamondoid, 0.8 mmol of N-hydroxyphthalimide (NHPI) and 0.6 mmolof acetylacetonatocobalt(II). The resultant mixture is stirred in anoxygen atmosphere at a temperature of 75° C. for about 3 hours. Thereaction is monitored by GC, allowing isolation of the monohydroxylatedhigher diamondoid upon completion.

Example 13

[0365] Polyhydroxylation of Higher Diamondoids

[0366] Into a 4-neck flask immersed in a cooling bath and equipted witha low temperature condenser (−20° C.), and an air driven, well sealedmechanical stirrer, a solid addition funnel and a thermocouple, is added0.037 mole of a higher diamondoid, 150 mL methylene chloride, 200 mLdouble distilled water, 192 grams sodium bicarbonate and 300 mLt-butanol. The mixture is stirred and cooled to 0° C. and 200 grams1,1,1-trifluoro-2-propanone (TFP) are added. The mixture is stirred andcooled down to −8° C. 200 grams oxone are added from the solid additionfunnel over the course of 3 hours. The reaction mixture is stirred at 0°C. overnight (16 hours). The TFP is recovered by distillation (heatingpot to 40° C. and condensing TFP in a receiver immersed in dryice/acetone). The remainder mixture is filtered by suction and a clearsolution is obtained. The solution is rotavapped to dryness, providing amixture of polyhydroxylated higher diamondoids that are purified bychromatography and/or recrystallization.

[0367] Via Substitution of Brominated Higher Diamondoids [D—(Br)_(n)] orHigher Diamondoid Substituted Bromides [e.g. D-(Alkyl-Br)_(n)]

Example 14

[0368] Monohydroxylated Higher Diamondoids from Monobrominated Compounds

[0369] A suitable monobrominated higher diamondoid (0.066 mol) is heatedto reflux for about 1 h in a round bottom flask, which is equipped witha stirrer and a reflux condenser, while stirring and adding 35 mL water,3.5 mL tetrahydrofuran, 2.0 g potassium carbonate and 1.3 g silvernitrate. After cooling, the reaction product, which has crystallized, isseparated out and is extracted with tetrahydrofuran. The extract isdiluted with water and the precipitate is suctioned off, dried andpurified by sublimation under vacuum.

[0370] Alternatively, a suitable monobromo higher diamondoid (0.1 mole)is mixed with 40 mL of 0.67 N hydrochloric acid and 450 mL DMF. Theresultant mixture is stirred at reflux temperature for about 1 hour. Thesolid product is filtered and recrystallized from n-hexane to producethe monohydroxylated higher diamondoid.

Example 15

[0371] Dihydroxylated Higher Diamondoids from Dibrominated Compounds

[0372] A suitable dibrominated higher diamondoid (0.066 mol) is heatedto reflux for about 1 h in a round bottom flask, which is equipped witha stirrer and a reflux condenser, while stirring and adding 70 mL water,10 mL tetrahydrofuran, 4.0 g potassium carbonate and 2.6 g silvernitrate. After cooling, the reaction product is separated out andextracted with tetrahydrofuran. The extract is diluted with water andthe precipitate is suctioned off, dried and purified by sublimationunder vacuum.

[0373] Alternatively, a mixture of a dibromo higher diamondoid (0.12mole) and 70% nitric acid (200 mL) is heated at 70-75° C. until bromineevolution ceases. The reaction mixture is poured into water (250 mL) andthe precipitate is filtered. The filtrate is made alkaline with 10%aqueous sodium hydroxide and the mixture is filtered. The combinedprecipitates are washed with water (3×200 mL) and acetone (2×150 mL) anddried to provide the desired compound.

Example 16

[0374] D—CH₂CH₂—OH from D—CH₂CH₂Br

[0375] A suitable D—CH₂CH₂—Br (0.066 mol) is heated to reflux for about1 h in a round bottom flask, which is equipped with a stirrer and areflux condenser, while stirring and adding 35 mL water, 3.5 mLtetrahydrofuran, 2.0 g potassium carbonate and 1.3 g silver nitrate.After cooling, the reaction product is separated out and is extractedwith chloroform. Evaporating the solvent affords the product afterpurification by column chromatography.

[0376] Via Reduction of Keto Higher Diamondoids (Higher Diamondoidones)for the Synthesis of C-2 Hydroxylated Higher Diamondoids (Substituted atthe Secondary Carbons)

Example 17

[0377] C-2 D—OH from D═O

[0378] A suitable higher diamondoidone D═O is reduced with lithiumaluminum hydride (a little excess) in ethyl ether at low temperatures.After completion of the reaction, the reaction mixture is worked up byadding saturated Na₂SO₄ aqueous solution to decompose excess hydride atlow temperature. Decantation from the precipitated salts gives a dryether solution, which, when evaporated, affords a crude C-2monohydroxylated higher diamondoid substituted at the secondary carbon,i.e. C-2 D—OH. Further recrystallization from cyclohexane gives a puresample.

[0379] Esterification of Hydroxylated Higher Diamondoids and HigherDiamondoid Substituted Alcohols

Example 18

[0380] Diesterified Higher Diamondoids from Dihydroxylated Compounds

[0381] To 2 mL of dioxane is added a dihydroxylated higher diamondoid(1.0 mmol) and triethylamine (2.2 mmol) at a temperature of 50° C. Theresultant mixture is added dropwise to a solution of acrylic acidchloride (2.2 mmol) in dioxane (2 mL). The mixture is maintained at 50°C. for about 1 hour. The product is analyzed by GC. When the analysisconfirms the formation of the desired diacrylate, the compound isisolated using standard methods.

Example 19

[0382] D—CH₂CH₂—OCOCH₃from D—CH₂CH₂—OH

[0383] To 2 mL of dioxane is added a D—CH₂CH₂—OH (1.0 mmol) andtriethylamine (2.2 mmol) at a temperature of 50° C. The resultantmixture is added dropwise to a solution of CH₃COCl (1.1 mmol) in dioxane(2 mL). The mixture is maintained at 50° C. for about 1 hour. Theproduct is analyzed by GC. When the analysis confirms the formation ofthe desired compound, the product is isolated using standard methods.

[0384] Synthesis of Keto Higher Diamondoids (Higher Diamondoidones,[D(═O)_(n)]) and Reactions Thereof

Example 20

[0385] Oxidation of Higher Diamondoids to Higher Diamondoidones

[0386] A solution of 11.0 mmol of a suitable higher diamondoid in 18.7 gof methylene chloride is mixed with 4.22 g of a solution of 1.03 g (13.5mmol) of peracetic acid in ethyl acetate. While being stirredvigorously, the solution is irradiated with a 100-watt UV light placedin an immersion well in the center of the solution. Gas evolution isevident from the start. The temperature is maintained at 40-45° C. foran about 21-hour irradiation period. At the end of this time, about 95%of the peracid had been consumed. The solution is concentrated to neardryness, treated twice in succession with 100-mL portions of toluene andreevaporated to dryness. Final drying in a desiccator affords a solid.

[0387] The crude, hydroxylated higher diamondoid mixture is thenpartially dissolved in acetone. The oxygenated components go into thesolution but not all of the unreacted higher diamondoid. Chromicacid-sulfuric acid solution is added dropwise until an excess ispresent, and the reaction mixture is stirred overnight. The acetonesolution is decanted from the precipitated chromic sulfate and theunreacted higher diamondoid, and is dried with sodium sulfate. Theunreacted higher diamondoid is recovered by dissolving the chromiumsalts in water and filtering. Evaporation of the acetone solutionaffords a solid. This crude solid is chromatographed on alumina withstandard procedures eluting first with 1:1 (v/v) benzene/light petroleumether followed by ethyl ether or a mixture of ethyl ether and methanol(95:5 v/v) to collect the unreacted higher diamondoid and the higherdiamondoidone, respectively. Further purification by recrystallizationfrom cyclohexane affords a pure higher diamondoidone.

Example 21

[0388] 2,2-Bis(4-hydroxyphenyl) Higher Diamondoids from Keto Compounds

[0389] A flask is charged with a mixture of a higher diamondoidone(0.026 mole), phenol (16.4 g, 0.17 mole), and butanethiol (0.15 mL).Heat is applied and when the reaction mixture becomes liquid at about58° C., anhydrous hydrogen chloride is introduced until the solutionbecomes saturated. Stirring is continued at about 60° C. for severalhours, during which period a white solid begins to separate out from thereaction mixture. The solid obtained is filtered off, washed withdichloromethane and dried to afford the bisphenol higher diamondoidproduct. It is purified by sublimation after recrystallization fromtoluene.

Example 22

[0390] 2,2-Bis(4-aminophenyl) Higher Diamondoids from Keto Compounds

[0391] To a solution of a higher diamondoidone (0.041 mole) in 15 mL of35% HCl aqueous solution in a 100 mL autoclave equipped with a stirreris added excess aniline (15.7 g, 0.17 mole) and the mixture is stirredat about 120° C. for about 20 hours. After cooling, the solution is madebasic with NaOH aqueous solution to pH 10 and the oily layer isseparated and distilled to remove the unreacted excess aniline. Theresidual crude product is recrystallized from benzene to afford thehigher diamondoid derived bisphenylamine.

Example 23

[0392] 2,2-Bis[4-(4-aminophenoxy)phenyl] Higher Diamondoids fromBisphenol Higher Diamondoids

[0393] A mixture of a 2,2-bis(4-hydroxyphenyl) higher diamondoid (0.01mole), p-fluoronitrobenzene (3.1 g, 0.022 mole), potassium carbonate(3.31 g, 0.024 mole) and N,N,-dimethylacetamide (DMAc, 10 mL) isrefluxed for about 8 hours. The mixture is then cooled and poured into aethanol/water mixture (1:1 by volume). The crude product is crystallizedfrom DMF to provide yellow needles of the2,2-bis[4-(4-nitrophenoxy)phenyl] higher diamondoid.

[0394] Hydrazine monohydrate (20 mL) is added dropwise to a mixture ofthe above product (0.002 mole), ethanol (60 mL), and a catalytic amountof 10% palladium on activated carbon (Pd/C, 0.05 g) at the boilingtemperature. The reaction mixture is refluxed for about 24 hours, andthe product 2,2-Bis[4-(4-aminophenoxy)phenyl] higher diamondoid isprecipitated during this period. The mixture is then added to enoughethanol to dissolve the product and filtered to remove Pd/C. Aftercooling, the precipitated crystals are isolated by filtration andrecrystallized from 1,2-dichlorobenzene.

[0395] Synthesis of Nitro Higher Diamondoids [D—(NO₂)_(n)] (n=1, 2, 3,4, . . . )

[0396] Via Direct Nitration Reaction of Higher Diamondoids

Example 24

[0397] Mononitration of Higher Diamondoids

[0398] A mixture of 0.05 mole of a higher diamondoid and 50 mL ofglacial acetic acid is charged to a stirred stainless 100 mL autoclavewhich is pressurized with nitrogen to a total pressure of 500 p.s.i.ga.After the mixture is then heated to 140° C., 9.0 g (0.1 mole) ofconcentrated nitric acid is introduced into the reaction zone by meansof a feed pump at a rate of 1-2 mL per minute. When the acid feed iscompleted, the reaction temperature is maintained at 140° C. for 15minutes, after which time the reaction mixture is cooled down to roomtemperature and diluted with an excess of water to precipitate theproducts. The filtered solids are slurried with a mixture of 10 mL ofmethanol, 15 mL of water, and 1.7 g of potassium hydroxide for 18 hoursat room temperature. After dilution with water, the alkali-insolublematerial is extracted by light petroleum ether. The petroleum etherextracts are washed by water and dried over anhydrous magnesium sulfate.Concentration of this solution affords a white solid. The aqueous alkalisolution from which the alkali-insoluble material had been extracted iscooled to 0-3° C. and neutralized by the dropwise addition of an aqueousacetic acid-urea mixture to regenerate some more products. GC analysisshows that the alkali-insoluble sample is mainly mononitro higherdiamondoid with a small amount of dinitro product. Recrystallizationfrom methanol and repeated sublimation, yields the mononitro higherdiamondoid.

[0399] Via Oxidation of Amino Higher Diamondoids [D—(NH₂)_(n)]

Example 25

[0400] Mononitro Higher Diamondoids from Monoamino Compounds

[0401] A suspension of 0.01 mole of a suitable monoaminated higherdiamondoid in 50 mL water is heated to 60° C. To this suspension isgradually added dropwise a solution of 3.5 g potassium permanganate in50 mL water (about 1 hour). After this has been added, the mixture isheated to reflux for about 2 hours, whereby the fraction sublimating inthe condenser is washed back in again. The crystals are purified twiceby sublimation under vacuum.

[0402] Synthesis of Higher Diamondoidyl Carboxylic Acids (HigherDiamondoidyl Acetic Acid) [D—(CO₂H)_(n)] (n=1, 2, 3, 4, . . . )

[0403] Via Direct Carboxylation Reaction of Higher Diamondoids

Example 26

[0404] Monocarboxylation of Higher Diamondoids

[0405] A mixture of 29.6 g (0.4 mole) tert-butanol and 55 g (1.2 mole)99% formic acid is added dropwise over about 3 hours to a mixture of 470g 96% sulfuric acid and 0.1 mole higher diamondoid dissolved in 100 mLcyclohexane while stirring vigorously at room temperature. Afterdecomposing with ice, the acids are isolated and purified byrecrystallization from methanol/water giving the monocarboxylated higherdiamondoid.

[0406] Via Brominated Higher Diamondoids [D—(Br)_(n)]

Example 27

[0407] D—COOH from D—Br

[0408] 360 mL concentrated sulfuric acid, which has been cooled to +10°C., is placed in a 1-L three-necked flask, which is equipped with astirrer, a reflux condenser and an Anschütz top with two droppingfunnels. After removing the ice bath, while stirring, a suitablemonobrominated higher diamondoid D—Br (0.056 mole) dissolved in 25 mLdry, highly pure n-hexane and 25.3 mL anhydrous formic acid is addedinto the flask in a course of about 1 hour. A fume hood is necessary toremove the carbon monoxide produced. After the dropwise addition hasbeen completed, the mixture is vigorously stirred for about anadditional 2 hours at room temperature. Then the reaction mixture ispoured onto ice, whereby the acid precipitates out. The acid is purifiedby dissolution in ether and extraction with dilute sodium hydroxideaqueous solution. The acid which precipitates during the acidificationis recrystallized from dilute methanol.

Example 28

[0409] D—CHClCOOH from D—Br

[0410] A mixture of a suitable monobrominated higher diamondoid D—Br(0.012 mole) and 9.0 g trichloroethylene CHCl═CCl₂ is added dropwise inthe course of about 4 hours into 24 mL 90% sulfuric acid at 103-106° C.while stirring. After the addition is completed, the mixture is stirredfor about an additional 2 hours at the specified-temperature, thencooled down and hydrolyzed with ground ice. The precipitated product canbe freed from the neutral fraction by dissolution in dilute sodiumhydroxide solution and extraction with ethyl ether. When acidified withdilute hydrochloric acid solution, the carboxylic acid precipitates outof the alkaline solution. Further purification could be achieved byrecrystallization from cyclohexane.

[0411] Via Hydroxylated Higher Diamondoids [D—(OH)_(n)]

Example 29

[0412] D—COOH from D—OH

[0413] When a monohydroxylated higher diamondoid D—OH is used, one worksin the same way described in Example 31 above except that the amount ofn-hexane must be increased to 150 mL because of the lower solubility ofthe monohydroxalted higher diamondoid in n-hexane.

Example 30

[0414] D—(COOH)₂ from D—(OH)₂

[0415] Formic acid (98%, 280 mL) is added dropwise to a stirred solutionof a dihydroxylated higher diamondoid D—(OH)₂ (0.091 mol) inconcentrated sulfuric acid (96%, 1.3 L) at 0° C. The mixture is stirredat 0 ° C. for 2 hours and at room temperature for 4 hours, and is thenpoured over ice/water. The resultant product is washed with water andacetone and dried to afford the dicarboxylated higher diamondoid.

[0416] Synthesis of Acylaminated Higher Diamondoids [D—(NHCOR)_(n)] (R═Hor alkyl, n=1, 2, 3, 4, . . . )

[0417] Via Brominated Higher Diamondoids [D—(Br)_(n)]

Example 31

[0418] D—NHCOCH₃ from D—Br

[0419] A suitable monobrominated higher diamondoid D—Br (0.093 mole) isdissolved in 150 mL acetonitrile. While stirring, 30 mL concentratedsulfuric acid is slowly added to the above solution, whereby the mixtureheats up. After it has been left standing for about 12 hours, thesolution is poured into 500 mL ice water, whereby the monoacetaminohigher diamondoid separates out.

[0420] Via Hydroxylated Higher Diamondoids [D—(OH)_(n)]

Example 32

[0421] D—NHCOCH₃ from D—OH

[0422] A suitable monohydroxylated higher diamondoid D—OH (0.046 mole)is dissolved in 120 mL highly pure glacial acetic acid and treated with13 mL acetonitrile and 4 mL concentrated sulfuric acid. The reactionmixture is left standing closed for about 20 hours at room temperature,and then twice the volume of water is added to it. After a few hours theprecipitated reaction product is filtered off, and after drying it isrecrystallized from cyclohexane.

[0423] Via Carboxylated Higher Diamondoids [D—(CO₂H)_(n)]

Example 33

[0424] D—NHCOCH₃from D—CO₂H

[0425] Within 12 minutes, 4.1 g (0.1 mole) acetonitrile and a suitablemonocarboxylated higher diamondoid D—COOH (0.018 mole) are added to 20mL 100% sulfuric acid at room temperature while stirring vigorously. Iceis added after about 1.5-hour post reaction. Then a crystallineprecipitate is separated out. The suspension is made basic with sodiumhydroxide solution and suctioned over a glass frit. Recrystallizationfrom cyclohexane affords a monoacetaminated higher diamondoid product.

Example 34

[0426] D—NHCHO from D—COOH

[0427] Within 7 minutes 8.16 g (0.17 mole) sodium cyanide and a suitablemonocarboxylated higher diamondoid D—COOH (0.028 mole) are added to 100mL 100% sulfuric acid while stirring vigorously. After ½ hour,decomposition is carried out by pouring the reaction mixture onto 250 gcrushed ice which is then made basic by the addition of a sufficientamount of odium hydroxide solution and extracted five times withbenzene/ether. The solvent is removed in vacuo from the combinedextracts and the residue is recrystallized from benzene/hexane to affordmonoformylaminated higher diamondoid D—NHCHO.

[0428] Synthesis of Higher Diamondoidyl Carboxylic Acid Esters[D—(CO₂R)_(n)] Via Esterification Reaction (R=alkyl, n=1, 2, 3, 4, . . .)

Example 35

[0429] D—CO₂CH₂CH₃ from D—COOH via D—COCl

[0430] 0.017 mole of a suitable monocarboxylated higher diamondoidD—COOH is mixed with 4.2 g PCl₅ in a 50-mL flask with a stirrer and areflux condenser. The reaction starts after 30-60 seconds withliquefaction of the reaction mixture. The mixture is heated for anadditional about 1 hour while stirring on the steam bath. The POCl₃formed is distilled off under vacuum. The acid chloride left behind as aresidue is cooled with ice water, and 6.0 mL absolute ethanol is addeddropwise. The mixture is heated for an additional around 1 hour on thesteam bath and then poured into 50 mL water after it has been cooleddown. The ester is taken up with ethyl ether and then washed withpotassium carbonate aqueous solution and water. After drying,fractionation is carried out over calcium chloride under vacuum.

[0431] Synthesis of Hydroxymethylated Higher Diamondoids[D—(CH₂—OH)_(n)] Via Reduction of Higher Diamondoidyl Carboxylic AcidEsters [D—(CO₂R)_(n)] (R=alkyl, n=1, 2, 3, 4, . . . )

Example 36

[0432] D—CH₂—OH from D—CO₂CH₂CH₃

[0433] 0.014 mole of a suitable higher diamondoid monocarboxylicacid-ethyl ester D—CO₂CH₂CH₃ dissolved in 10 mL absolute ether is slowlyadded dropwise to a suspension of 0.8 g lithium alanate in 16 mLabsolute ether while stirring at room temperature. The mixture isstirred for an additional about 1 hour and then water is carefullyadded. The ether solution is separated out and the aqueous phase isextracted with ether two more times. After the combined extracts havebeen dried with calcium chloride, the ether is distilled off and theresidue is recrystallized from methanol/water.

[0434] Synthesis of Aminated Higher Diamondoids [D—(NH₂)_(n)] (n=1, 2,3, 4, . . . )

[0435] Via Alkaline Hydrolysis of Acylaminated Higher Diamondoids[D—(NHCOR)_(n)] (R=alkyl, e.g. CH₃)

Example 37

[0436] D—NH₂ from D—NHCOCH₃

[0437] A suitable monoacetaminated higher diamondoid D—NHCOCH₃ (0.015mole) is heated to reflux for about 5 hours with a solution of 6 gpowdered sodium hydroxide in 60 mL diethylene glycol. After it has beencooled down, the mixture is poured into 150 mL water and extracted withethyl ether. The ether extract is dried with potassium hydroxide. Theether is distilled off and the residue is sublimated to afford theproduct monoaminated higher diamondoid. The hydrochloride salt isprepared for analysis. Thus, dry hydrogen chloride is conducted into theether solution of the amine, whereby the salt separates out as acrystalline compound. It can be purified by dissolving it in absoluteethanol and precipitating with absolute ether.

Example 38

[0438] D—NH₂fro D—Cl

[0439] A suitable monochlorinated higher diamondoid D—Cl is converted bythe acetonitrile-sulfuric acid procedure described above to themonoacetaminated higher diamondoid D—NHCOCH₃. The crude amide, withoutprior purification, is saponified to afford a monoaminated higherdiamondoid D—NH₂. Purification of the amine is as described above.

Example 39

[0440] D—NH₂ from D—COOH

[0441] Step 1: 0.017 mole of a suitable monocarboxylated higherdiamondoid D—COOH is mixed with 4.2 g PCl₅ in a 50-mL flask with astirrer and a reflux condenser. The reaction starts after 30-60 secondswith liquefaction of the reaction mixture. The mixture is heated for anadditional about 1 hour while stirring on the steam bath. The POCl₃formed is distilled off under vacuum to afford an acid chloride D—COCl.

[0442] Step 2: a solution of the above higher diamondoidylmonocarboxylic acid-chloride D—COCl (0.027 mole) in 12 mL absolutetetrahydrofuran is slowly added dropwise to a 60 mL concentrated aqueousammonia solution while stirring and cooling with ice water. The higherdiamondoidyl monocarboxylic acid-amide is separated out as aprecipitate. It is suctioned, washed with water and recrystallized fromcyclohexane after it has been dried.

[0443] Step 3: 0.018 mole of the above amide is dissolved in 25 mLabsolute methanol. This solution is added to a solution of 1.0 g sodiumin 25 mL absolute methanol, which is located in a 150-mL three-neckedflask with a stirrer, a reflux condenser and dropping funnel. Then 1.0mL bromine is added dropwise with ice cooling, and then the mixture isslowly heated to around 55° C. (water bath temperature). After it hasbeen cooled, water is added and the precipitate is separated out byfiltration. Further purification can be achieved by recrystallizationfrom ethanol.

[0444] Step 4: the above product is finally saponified and worked up inthe same way as described above to afford the target compound.

[0445] Via Acid Hydrolysis of Formylaminated Higher Diamondoids[D—(NHCHO)_(n)]

Example 40

[0446] D—NH₂ from D—Br via D—NHCHO

[0447] Step 1: a monobromo higher diamondoid D—Br (0.028 mol) is mixedwith 40 mL formamide. The resultant mixture is refluxed for about 12hours. After cooling, the reaction mixture is poured into water andextracted with dichloromethane. The organic phase is dried withmagnesium sulfate, filtered, and evaporated to dryness under vacuum toprovide a mono N-formyl higher diamondoid D—NHCHO.

[0448] Step 2: the above mono N-formyl higher diamondoid D—NHCHO (0.023mol) is mixed with 100 mL of 15% hydrochloric acid. The resultantmixture is heated to boiling for about 24 hours. After cooling, theprecipitate is filtered and recrystallized from isopropanol to affordthe product D—NH₂.

[0449] Via Reduction of Nitro Higher Diamondoids [D—(NO₂)_(n)]

Example 41

[0450] D—NH₂ from D—NO₂

[0451] A mixture of 0.412 mmol of a mononitro higher diamondoid D—NO₂and 11.5 g of sodium sulfide nonahydrate in 400 mL of mixed solvent ofTHF/H₂O (3:2 v/v) is vigorously stirred for about 12 hours at 75 ° C.After cooling to room temperature, the mixture is concentrated below 40°C. under reduced pressure until the volume is reduced to about 15 mL.The precipitate is filtered with suction followed by washing well withwater and a 1.0 N HCl aqueous solution. The crude product is dissolvedin chloroform or ethyl ether and washed with water (4×80 mL) toneutralize any sodium hydroxide in the organic phase until the materialis free from sodium hydroxide and sodium chloride. After removal of thesolvent, a crude product is obtained. The separation and purification ofthe product is carried out on column chromatography on neutral Al₂O₃using chloroform/hexane as the eluent. If necessary, purification oncolumn chromatography could be performed several times.

[0452] Synthesis of Alkenylated Higher Diamondoids Via Alkylation andDehydrogen Bromide Reactions

Example 42

[0453] D—CH═CH₂from D—Br

[0454] Step 1: a solution of a suitable monobrominated higher diamondoid(D—Br) (0.046 mole) in 15 mL n-hexane in a 150-mL three-necked flaskequipped with a stirrer, a gas inlet tube and a gas discharge tube witha bubble counter is cooled to −20 to −25° C. in a cooling bath. Whilestirring one introduces 4.0 g powdered freshly pulverized aluminumbromide of high quality, and ethylene is conducted in such a way thatthe gas intake can be controlled with the bubble counter. The reactionstarts with a slight darkening of the color and is completed after about1 h. The reaction solution is decanted from the catalyst into a mixtureof ether and water. The ether layer is separated off, and the aqueousphase is extracted once more with ether. The combined ether extracts arewashed with water and dilute sodium carbonate aqueous solution. Afterthey have been dried over calcium chloride, the ether is distilled off.The residue is separated by distillation under vacuum. An oily liquid isdistilled and collected, which solidifies in the receiver.Recrystallizing from methanol affords the higher diamondoidyl ethylbromide D—CH₂CH₂Br.

[0455] Step 2: a solution of 0.7 g fine powdered potassium hydroxide andthe above higher diamondoidyl ethyl bromide D—CH₂CH₂Br (0.012 mole) in10 mL diethylene glycol is heated to 220° C. in an oil bath for 6 hours.After cooling down the mixture is diluted with 30 mL water and exactedwith ethyl ether. The ether extract is washed twice with water and driedover calcium chloride. The residue left behind after the ether has beendistilled off is sublimated in vacuum, and if necessary, the compoundcan be recrystallized from methanol.

[0456] Synthesis of Alkynylated Higher Diamondoids Via Alkylation andDehydrogen Bromide Reactions

Example 43

[0457] D—C≡CH from D—Br

[0458] Step 1: in a 150-mL two-necked flask with a stirrer and a dryingtube, a mixture of 0.069 mole of a suitable monobromonated higherdiamondoid and 20 mL vinyl bromide is cooled to −65° C. in a coolingbath. While stirring, 4.5 g powdered aluminum bromide is added inportions and the mixture is stirred for an additional about 3 hours atthe same temperature. Then the reaction mixture is poured into a mixtureof 30 mL water and 30 mL ethyl ether. After vigorously stirring, theether layer is separated and the aqueous layer is extracted once morewith ether. The combined ether extracts are washed with water and dilutesodium carbonate solution. After it has been dried with calcium chlorideand the solvent has been distilled off, the residue is distilled undervacuum.

[0459] Step 2: 15 g powdered potassium hydroxide in 30 mL diethyleneglycol is heated to reflux with 0.046 mole of the above product forabout 9 hours in the oil bath. Monoethynylated higher diamondoid isformed and may condense in the condenser and must be returned to thereaction mixture from time to time. At the end of the reaction time, thereaction mixture is distilled until no more solid particles go over. Thedistillate is extracted with ethyl ether and the ether phase is washedwith water and dried over calcium chloride. The ether is distilled offand, the residue solidifies. It may be sublimated under vacuum and, ifnecessary, recrystallized from methanol.

Example 44

[0460] D—C≡CH and D—(C≡CH)₂ from D—Br

[0461] A solution of a monobromo higher diamondoid D—Br (14.2 mmol) andvinyl bromide (5 mL) in CH₂Cl₂ (25 mL) is cooled with a dry ice-acetonebath (−30° C.). aluminum bromide (4.9 mmol) is added, portionwise, over30 minutes while the internal temperature is kept below −24° C. themixture is stirred at −30° C. for 45 min., diluted with CH₂Cl₂ andsolwly poured over crushed ice and concentrated hydrochloric acid (20mL). The organic layer is separated and the aqueous layer is extractedwith CH₂Cl₂. The combined organic layers are washed with brine, driedand filtered. Solvent is evaporated under reduced pressure to give aviscous oil.

[0462] The oil is dissolved in DMSO (50 mL) and potassium t-butoxide (36mmol) is added over 1 hour. The mixture is stirred at room temperaturefor 3 days and then heated at 50-55° C. for 3.5 hours. Standardisolation procedure with CH₂Cl₂ gives an oil. Distillation provides asemi-solid residue. The residue is chromatographed on silica gel (hexaneand 95:5 hexane/CH₂Cl₂) to afford the mono-(D—C≡CH) and diethynylatedhigher diamondoid D—(C≡CH)₂.

[0463] Synthesis of Higher Diamondoidyl Ethers [D—(OR)_(n)] (n=1, 2, 3,4, . . . ; R is alkyl, aryl, etc.)

Example 45

[0464] D—O—CH₂—C₆H₅ from D—Br

[0465] To a solution of benzyl alcohol C₆H₅—CH₂—OH (0.28 mole)containing 0.03 mole of sodium benzylate is added 0.01 mole of D—Br andthe resulting mixture heated for about 4 hours, during which a copiousprecipitate NaBr formed. After cooling, the reaction mixture is pouredinto water and the aqueous phase extracted with ethyl ether and thelater dried over sodium sulfate, then evaporated. Most of the benzylalcohol is removed by distillation, leaving ca. 4 mL of oil which ischromatographed over alumina. Elution with petroleum ether affords theproduct.

[0466] Sequential Reactions of Higher Diamondoidyl Acetic Acid and TheirDerivatives

[0467] As shown above, the higher diamondoidyl carboxylic acid, e.g.D—COOH, can be conveniently prepared by different methods. Thecorresponding acid chloride D—COCl is obtained by stirring a mixture ofthe acid and thioyl chloride diluted with petroleum ether at roomtemperature for about 50 hours. Treatment of the acid chloride D—COClwith an excess amount of ethereal diazomethane gives the higherdiamondoidyl acetyl diazomethane D—COCHN₂. Reactions of the acidchloride D—COCl with such amines as ammonia and aniline give thecorresponding amides, in those cases D—CONH₂ and D—CONHC₆H₅respectively, in good yields.

[0468] The Hofmann reaction of D—CONH₂ with bromine and alkali affordsD—NHCONHC(O)—D via the isocyanate intermediate D—NCO.

[0469] The acid chloride D—COCl and hydrazine hydrate hive thecorresponding bishydrazide (D—CONH)₂, while methyl higherdiamondoidylacetate D—COOCH₃ and hydrazine hydrate give monohydrazideD—CONHNH₂. The lithium aluminum hydride reduction of D—COOCH₃ givesD—CH₂—OH. Those reactions are summarized in FIG. 20.

Example 46

[0470] D—CONH₂ from D—COCl

[0471] Concentrated aqueous ammonia (11.0 mL) is, over a period of 30min., stirred, drop by drop, into a stirred solution of D—COCl, preparedfrom 5.5 mmole of D—COOH, in 4.0 mL of dry THF under cooling withice-water. The stirring is continued for about 6 hours, and then, theprecipitates are filtered out washed with water and dried to give thetitle compound.

Example 47

[0472] Hofmann Reaction of D—CONH₂

[0473] Into an ice-cooled bromine-alkali reagent, freshly prepared from1.0 g of bromine, 1.0 g of sodium hydroxide, and 10 mL of water, 0.5 gof D—CONH₂ is added and stirred. The temperature is then raised to about80° C. over a 3.5-h period and kept there for about 10 min. aftercooling, separated solids are filtered and washed with water.Recrystallization from chloroform-petroleum ether gives the pure productD—NHCONHC(O)—D.

Example 48

[0474] D—CONH—C₆H₅from D—COCl

[0475] A mixture of D—COCl, prepared from 2.8 mmole of D—COOH, 0.5 g ofaniline, and 20 mL of dry benzene, is refluxed for about 15 min. andcooled. The cooled reaction mixture is washed with 5% hydrochloride acidand then with water, and dried over anhydrous sodium sulfate. After theremoval of the solvent, the residue is recrystallized from methanol togive the product D—CONH—C₆H₅.

Example 49

[0476] (D—CONH)₂ from D—COCl

[0477] Into an ice-cooled solution of 1.6 g of 80% hydrazine hydrate in1.0 mL of THF is stirred and stirring is continued for about 7 hours atroom temperature. The then the mixture is allowed to stand in arefrigertor overnight. Solids are then filtered and recrystallized frommethanol to give the product (D—CONH)₂.

Example 50

[0478] D—CON₃, D—NCO, and D—NHCONH—C₆H₅ from D—COCl

[0479] Into a solution of D—COCl, prepared from 2.8 mmole of D—COOH, in2 mL of acetone, a solution of 2.0 g of sodium azide in 5 mL of water isstirred. Stirring is continued for about 2 hours at room temperature.The reaction mixture is then diluted with 15 mL of water and extractedwith ethyl ether (2×30 mL). The combined ether extracts are washed withwater, dried over anhydrous sodium sulfate, and evaporated to give acompound which by an infrared analysis shows that the rearrangement hasalready occurred during the procedure. To complete the rearrangement,the crude azide D—CON₃ is heated in dry denzene for about 1 hour.

[0480] The crude azide D—CON₃ is treated with 0.30 mL of aniline inn-hexane at room temperature for about 13 hours. The precipitates arethen filtered to give a crude D—NHCONH—C₆H₅.

Example 51

[0481] D—CH₂CONH—C₆H₅ from D—COCl via D—COCHN₂

[0482] A soultion of D—COCl, prepared from 2.8 mmole of D—COOH, in 10 mLof ether is added to a solution of diazomethane in 100 mL of ether underice-water cooling, after which the reaction mixture is allowed to atandfor about two days at room temperature. The solvent is stripped off invacuo, and the residual compound, D—COCHN₂, is characterized as having adiazoketone structure on the basis of the infrared absorptions, D—COCHN₂and 0.7 g of aniline are dissolved in 100 mL of anhydrous benzene, andthe mixture is irradiated with a 100-W high-pressure mercury lampthrough a quartz cooler in a nitrogen stream at room temperature. Afterabout 9 hours' irradiation, the solution is washed successively with 10%hydrochloric acid, 5% sodium hydroxide, and then water. The solution isdried over anhydrous sodium sulfate, and th benzene is distilled off invacuo. The residue is triturated with 10 mL of n-hexane to give a purercompound. The isolated compound is dissolved in 50 mL of ethanol, andthe solution is treated with active charcoal. The solvent is distilledoff in vacuo, and the residue is recrystallized from methanol to affordthe pure product D—CH₂CONH—C₆H₅.

Example 52

[0483] D—CH₂—OH from D—COOH via D—COOCH₃

[0484] To an etheral solution of diazomethane, a solution of 2.8 mmoleof D—COOH in 20 mL of ether is gradually aded. The solution is allowedto stand overnight at room temperature, and then the ether is removed invacuo to give D—COOCH₃, which is then dissolved in 50 mL of dry ether,and then 1.1 g of lithium aluminum hydride is added to the solution. Thereaction mixture is then stirred overnight at room temperature anddiluted with 50 mL of water. The aqueous solution is acidified withconcentrated hydrochloric acid and extracted with ether. The etherextract is washed with water and dried over anhydrous sodium sulfate.The ether is removed to give the product D—CH₂—OH.

[0485] Synthesis of Bi-Higher Diamondoids [e.g. D—D] and Some of TheirDerivatives [e.g. R—D—D—R] (R═H, Br, CN, COOH, COCl, COOCH₃, CH₃OH,C₆H₄OCH₃, C₆H₄OH, C₆H₅, CH₂NH₂, CH₂NH₂HCl, OH, etc.)

Example 53

[0486] D—D from D—Br

[0487] A suitable monobrominated higher diamondoid D—Br (50 mmole) isdissolved in 30 mL of xylene and heated to reflux in a three-neckedflask fitted with thermometer, nitrogen inlet, stirrer, and refluxcondenser, under a slow stream of nitrogen. Then a total of 1.15 g ofsodium metal is added to the stirred reaction mixture over a period ofabout 4 hours. After all the sodium has been added, the mixture isrefluxed for about an additional hour and then filtered in the hotstate. On cooling to room temperature, the product D—D is crystallizedfrom the filtrate.

Example 54

[0488] Br—D—D—Br from D—D

[0489] D—D (14 mmole) is charged into a round-bottom flask fitted with areflux condenser. Then 20 mL of bromine is added with stirring, andhydrogen bromide is formed. Hydrobromic acid evolution ceases afterabout 15 min. The reaction mixture is then heated to reflux (ca. 61° C.pot temperature) for about 2 hours. The cooled reaction product isdiluted with 75 mL of CCl₄ and transfered to a separatory funnel, shakenwith ice-water, and sodium bisulfite is added until excess bromine isdestroyed. The organic layer is separated and the water layer isextracted twice with 50 mL of CCl₄. The combined organic solution isdried over sodium sulfate and the solvent is tripped under slightvacuum. The reaction product in the pot is precipitated with methanol,filtered off, and recrystallized from dioxane to give Br—D—D—Br product.

Example 55

[0490] NC—D—D—CN from Br—D—D—Br

[0491] To 15 g of cuprous cyanide charged into a round-bottom flaskfitted with a distilling bead, thermometer, and stirrer, 75 mL ofpyridine is added. To the pyridine-copper cyanide complex which hasformed immediately, Br—D—D—Br (46 mmole) is added and the reactionmixture heated slowly to about 230° C., whereby most of the pyridinedistilled. The reaction product is maintained at the above temperaturefor an additional 10 min. after cooling to room temperature, a crudeproduct is collected which is purified by recrystallization from benzeneto give a pure product NC—D—D—CN.

Example 56

[0492] HOOC—D—D—COOH from NC—D—D—CN

[0493] To 6.5 mmole of NC—D—D—CN is added a mixture of 15 mL ofconcentrtated sulfuric acid, 15 mL of glacial acetic acid, and 15 mL ofwater. The mixture is then heated to reflux for about 1.5 hours (about125° C. pot temperature) with stirring. The reaction product is filteredoff, carefully washed with water and methanol, and then dried.Recrystallization from dimethylacetamide affords the pure productHOOC—D—D—COOH.

Example 57

[0494] CH₃OC₆H₄—D—D—C₆H₄OCH₃ from Br—D—D—Br

[0495] To Br—D—D—Br (11.5 mmole) is added 25 mL of anisole and themixture is heated to reflux (about 155° C. pot temperature) for about 5hours. After about 15 minutes refluxing, hydrogen bromide is evolved.The evolution of hydrogen bromide iceases after about 1 hour. Thereaction product is filtered hot and on cooling to room temperature, acrude product is collected which is then recrystallized from xylene togive the pure product CH₃OC₆H₄—D—D—C₆H₄OCH₃.

Example 58

[0496] HClH₂NCH₂—D—D—CH₂NH₂HCl and H₂NCH₂—D—D—CH₂NH₂ from NC—D—D—CN

[0497] Powdered lithium aluminum hydride (0.6 g) is charged into athree-neck flask fitted with a thermometer, nitrogen inlet, additionfunnel, and reflux condenser together with 15 mL of anhydrous THF. Asolution of NC—D—D—CN (7.8 mmole) in 20 mL of anhydrous THF is addedover a period of about 20 min. the reaction product, after cooling toroom temperature, is poured onto ice containing dilute hydrochloricacid. Recrystallization from dilute hydrochloric acid gives thedihydrochloride product HClH₂NCH₂—D—D—CH₂NH₂HCl. The free diamineH₂NCH₂—D—D—CH₂NH₂ is obtained from the dihydrochloride by reaction withammonia.

[0498] Synthesis of Azido Higher Diamondoids [D—(N₃)_(n)] (n=1, 2, 3, 4,. . . )

[0499] Direct substitution of brominated higher diamondoids with NaN₃results in the formation of azido higher diamondoids, which are verygood precursors of higher diamondoidylnitrenes. The azido derivative,e.g. D—N₃, is reduced by lithium aluminium hydride in ether to give thecorresponding amine, e.g. D—NH₂.

Example 59

[0500] D—N₃from D—Br

[0501] A mixture of D—Br (2 mmole) and sodium azide (1.3 g) in drydimethyl sulfoxide (DMF, 20 mL) is heated with stirring at 100° C. forabout two days. The mixture is poured onto ice-water to give aprecipitate which can be purified by recrystallization from aqueousmethanol to give the pure product.

[0502] Synthesis of N—R-Sulfonyl-N′-Higher Diamondoidyl Ureas (e.g.R—SO₂NHCONH—D, R=alkyl, aryl, alkaryl, etc.)

Example 60

[0503] Aryl-SO₂NH₂from Aryl-SO₂—Cl

[0504] Aryl-SO₂NH₂ (arylsulfonamide) is prepared by addition ofAryl-SO₂—Cl (arylsulfonyl chloride) to a large excess of aqueousammonium hydroxide. It is better to dissolve the solid sulfonylchlorides in a volume of dioxane equal to their weight.

Example 61

[0505] Aryl-SO₂NHCOOCH₂CH₃ from Aryl-SO₂NH₂

[0506] To a mixture of 0.5 mole of the sulfonamide Aryl-SO₂NH₂ and 1.3moles of anhydrous potassium carbonate in 600 mL of acetone is added,during about 3 hours, with stirring, 0.66 mole of ethyl chlorocarbonateCl—COOCH₂CH₃. The mixture is then stirred and refluxed for about 18hours, then allowed to cool, and filtered. The solid residue isdissolved in about 1500 mL of water. Any insoluble material is removedby filtration. The solution is acidified with concentrated hydrochlorideacid. If the product does not crystallize readily, decantation of theacidic supernatant liquid and stirring the carbamate with water promotesthe crystallization. The crude product Aryl-SO₂NHCOOCH₂CH₃ (ethylN-arylsulfonylcarbamate) is used for reaction with a suitable amine,e.g. D—NH₂.

Example 62

[0507] Aryl-SO₂NHCO—NHD from Aryl-SO₂NHCOOCH₂CH₃ and D—NH₂

[0508] A solution of 2 mmoles of D—NH₂ and 2.2 mmoles ofaryl-SO₂NHCOOCH₂CH₃ (ethyl N-arylsulfonylcarbamate) in about 10 mL ofdry toluene is heated to reflux for about 5 hours. The reaction mixtureis allowed to cool to room temperature, and the product is collected byfiltration and then dissolved in chloroform (the chloroform should notcontain any trace amount of ethanol by shaking with alumina). Thechloroform solution is washed with cold 5% hydrochloric acid solution,then with water until neutral, and dried over anhydrous magnesiumsulfate. The chloroform solution is then concentrated under reducedpressure to about one-half its volume, warmed to about 50° C. Petroleumether is added. After chilling the mixture overnight, the productaryl-SO₂NHCO—NHD (N-arylsulfonyl-N′-higher diamondoidyl urea) iscollected by filtration.

[0509] Synthesis of Higher Diamondoidyl Chloroformates [D—(OCOCl)_(n)](n=1, 2, 3, 4, . . . ) and the Subsequent Reactions and Derivatives[e.g. D—OCONH₂, D—OCO—NHNH₂, etc.]

[0510] Higher diamondoidyl chloroformates, e.g. D—OCOCl, are preparedfrom hydroxylated higher diamondoids, e.g. D—OH, and excess phosgene(COCl₂) in a suitable solvent, e.g. benzene, in the presence of anorganic base, e.g. pyridine. The chloroformate is able to react withdifferent nucleophiles, e.g. ammonia, hydrazine (H₂NNH₂), amines, aminoacids, alcohols, thiols, etc., to give the corresponding higherdiamondoidyloxycarbonyl derivatives, e.g. D—OCONH₂, D—OCONHNH₂, etc. Thehigher diamondoidyloxycarbonylamino acids, in turn, are readily cleavedby acid-catalyzed solvolysis with, e.g. trifluoroacetic acid to yieldthe free amino acids. In those cases, the higher diamondoidyloxycarbonylgroup.

Example 63

[0511] D—OCOCl from D—OH

[0512] To a solution of liquid phosgene (COCl₂, 30 g) in anhydrousbenzene (100 mL), a solution of D—OH (53 mmoles) and pyridine (7 g) inbenzene (200 mL) is added dropwise and with stirring over a 1-h period,while maintaining the reaction temperature at about 4° C.

[0513] The reaction mixture is filtered and the filtrate is poured intoice water and shaken in a separatory funnel. The organic layer is driedwith sodium sulfate and concentrated to about one-fifth of its originalvolume under reduced pressure at room temperature.

[0514] When a sample of the concentrate is evaporated to dryness at roomtemperature, the solid is obtained. Recrystallization from anhydrouspetroleum may give crystals of the product.

Example 64

[0515] D—OCONHNH₂ from D—OCOCl and H₂NNH₂

[0516] A solution of D—OCOCl (9.3 mmoles) in anhydrous benzene (150 mL)is added slowly to a stirred solution of anhydrous hydrazine (2.5 g) int-butyl alcohol (20 mL). After stirring for about 2 hours, the solventis removed in vacuo. The residue is dissolved in a mixture of ether (150mL) and water (10 mL). The ether layer is washed with 35 mL portions ofwater, 5 mL of 1% sodium carbonate solution, and 5 mL of water, anddried. Anhydrous hexane (10 mL) is added and the solution isconcentrated to about 10 mL. Cooling the solution at about −10° C. givesthe product D—OCONHNH₂.

Example 65

[0517] D—OCONH₂ from D—OCOCl

[0518] A solution of D—OCOCl (0.5 mmole) in anhydrous benzene (25 mL) issaturated with gaseous ammonia (ca. 1 hour). The flask is stoppered andmaintained at ambient temperature for about 24 hours. The reactionmixture is filtered, and the filtrate is shaken with ice water andevaporated in vacuo to yield the product. Purification may berecrystallized from anhydrous ethanol.

Example 66

[0519] Higher Diamondoidyloxycarbonyl Amino Acids from D—OCOCl and AminoAcids

[0520] A suitable amino acid (5 mmoles) is suspended in water (about 20mL). The mixture is stirred and cooled in an ice bath. Sodium hydroxide(1N, 5 mL) is added whereupon the amino acid usually dissolved. To thismixture, 0.8 g sodium carbonate (7.5 mmoles) is added. From a solutionof D—OCOCl, the solvent is removed in vacuo on a flash evaporator at abath temperature of about 30° C. To the residue which may be oily orsemisolid, dry petroleum ether is added and removed in vacuo. This isrepeated once more to remove traces of phosgene which may be left in thepreparation of the chloroformate. The residue is dissolved in anhydrousdioxane (5 mL) and added to the solution of the amino acid over a periodof about 1 hour with continued stirring and cooling. Since some solidmay precipitate, ether is added (5 mL) after the first and last additionof the chloroformate. After stirring in ice for about 2 hours, thesolution is extracted three times with ether or ethyl acetate, and understirring and cooling acidified with 85% phosphoric acid or 10% sulfuricacid to a pH of about 2. The precipitated product is extracted into theorganic layer and the aqueous phase is extracted with two more portionsof fresh organic solvent. The combined extracts are dried over sodiumsulfate and the solvent is removed in vacuo. The residue isrecrystallized from a suitable solvent, e.g. ether-petroleum ether,ethyl acetate, ethyl acetate-petroleum ether.

[0521] Synthesis of Hydrazino Higher Diamondoids [e.g. D—(NH—NH₂)_(n)]Starting from Aminated Higher Diamondoids [e.g. D—(NH₂)_(n)] (n=1, 2,3,4, . . . )

[0522] D—(NH₂)_(n) and D—(CONH₂)_(n) (n=1, 2, 3, 4, . . . ) are veryimportant precursors for the synthesis of a variety of higher diamondoidderivatives. Some representative pathways for such a derivatization ofhigher diamondoids starting from D—NH₂ and D—CONH₂ are shown in FIG. 18.

Example 67

[0523] D—NH—CH₂—CN from D—NH₂

[0524] 40.5 mmoles of monoamino higher diamondoid hydrochloride(D—NH₂HCl) is dissolved in 80 mL water, then 3.2 g aqueous CH₂O solution(37-40%) is added with stirring at room temperature. While stirring atroom temperature, to the above mixture is added dropwise a solution of2.6 g potassium cyanide (KCN) in 20 mL water. A solid precipitate isformed and the mixture is stirred over night. Usual workup by extractingthe reaction mixture with chloroform and evaporating the solvent gives acrude product of D—NH—CH₂—CN (N-higher diamondoidyl aminoacetonitrile)and directly used for the next reaction without purification.Recrystallization from a little mixture of ethyl ether/light petroleumether gives a pure sample for analysis.

Example 68

[0525] D—NH—CH₂—COOH from D—NH—CH₂—CN

[0526] About 40 mmoles of the above crude product of D—NH—CH₂—CN ismixed with 50 mL water, 50 mL glacial acetic acid and 50 mL concentratedhydrochloric acid and then the mixture is heated to reflux. A reactionsolution (part A) and a crystalline sublimate (part B) formed in thereflux condenser are obtained.

[0527] Part A: after the reaction has lasted for about 6 hours, all thesolvent is removed under vacuum until a dry residue is obtained, whichis used directly for the next reaction. The product D—NH—CH₂—COOH can beeasily isolated by dissolving the dry residue in water and adjusting thepH to 4.

[0528] Part B: the sublimate is dissolved in chloroform, dried, and thesolvent evaporated to give, after recrystallizing from isopropanol andsublimating, a pure D—Cl as a major by-product.

Example 69

[0529] D—N(NO)—CH₂—COOH from D—NH—CH₂—COOH

[0530] The above crude product of D—NH—CH₂—COOH is dissolved in 100 mL 2N hydrochloric acid and a solution of 5 g sodium nitrite (NaNO₂) in 20mL water is added slowly drop by drop while stirring at roomtemperature. Solids precipitate and filtered out after the solution hasbeen standing over night, washed well with water and dried to afford theproduct of D—N(NO)—CH₂—COOH.

Example 70

[0531]

[0532] from D—N(NO)—CH₂—COOH

[0533] 11.5 mmoles of D—N(NO)—CH₂—COOH are treated with 25 mL of(CF₃CO)₂O. The solution is warmed up slightly after the treatment. Afterstanding for about 1 hour at room temperature, the solvent is removedunder vacuum. The residue is then extracted with chloroform and washedwell with 10% aqueous sodium bicarbonate solution. Evaporating thechloroform solvent affords a crude product. Recrystallization frommethanol gives the product.

Example 71

[0534] D—NH—NH₂ from

[0535] A suspension of about 39 mmoles of the above product in a mixtureof 150 mL alcohol and 100 mL concentrated hydrochloric acid is heated onan oil bath to reflux for 15 min. The solution is refluxed for anadditional around 45 minutes and then concentrated by evaporation. Theresidue is recrystallized from about 130 mL isopropanol to affordD—NH—NH₂HCl (monohydrazino higher diamondoid hydrochloride).

[0536] To produce the HCl free product D—NH—NH₂, the hydrochlorideproduct is dissolved in water and a little saturated potassium carbonatesolution is then added. A precipitate is filtered out with suction.Recrystallization from ether gives a pure product of D—NH—NH₂.

[0537] Synthesis of Higher Diamondoidyl Phosphonic Acid Dichlorides[e.g. D—(POCl₂)_(n)] and Subsequent Reactions and Derivatives Thereof(n=1, 2, 3, 4, . . . )

[0538]FIG. 19 presents some representative pathways for the synthesis ofa higher diamondoidyl phosphonic acid dichloride (e.g. D—POCl₂) and itssubsequent reactions and the corresponding derivatives, such as D—PH₂,D—PO(OH)₂, and so on.

Example 72

[0539] D—POCl₂ from D—Br

[0540] 0.1 mole of D—Br, 40 g (0.15 mol) of AlBr₃ and 200 mL of PCl₃ areheated for about 5 hours under reflux while being stirred. After coolingdown and filtration, the residue is washed with 100 mL of benzene,suspended in 300 mL of CCl₄ and decomposed carefully with water whilecooling with ice. The organic phase is separated out, washed with water,dried over CaCl₂ and concentrated in vacuum. Separation and purificationof the product D—POCl₂ can be conducted by distilling the residue andrecrystallization from acetone.

Example 73

[0541] D—PO(OH)₂ from D—POCl₂

[0542] Method A: 20 mmoles of D—POCl₂ is heated for about 6 hours with100 mL water under reflux. The aqueous solution is filtered aftercooling, and the residue is recrystallized from glacial acetic acidaffording the product D—PO(OH)₂.

[0543] Method B: 0.1 mole of D—POCl₂ in 100 mL ethanol is treated with200 mL concentrated hydrochloric acid and heated for about 5 hours underreflux. After cooling and filtration, the residue is recrystallizedseveral times from glacial acetic acid to give a pure product ofD—PO(OH)₂.

Example 74

[0544] D—PH₂ from D—POCl₂ via Reduction Reaction with LiAlH₄

[0545] Under nitrogen a solution of 0.1 mole of D—POCl₂ in 150 mLabsolute ether is added dropwise over a period of about 2 hours to asuspension of 7 g LiAlH₄ in 400 mL absolute ether. After the addition,the mixture is stirred for an additional 1 hour under reflux. The excessLiAlH₄ is destroyed by adding about 200 mL dilute hydrochloric acid. Theorganic phase is separated out, washed with water, dried over MgSO₄ andconcentrated under nitrogen. The residue is fractionated under nitrogenin vacuum to give the product D—PH₂.

Example 75

[0546] D—P(OH)₂ from D—PH₂ via Oxidation Reaction with H₂O₂

[0547] About 50 mmoles of D—PH₂ is heated carefully at approximately 50°C. with 50 mL of 30% hydrogen peroxide (H₂O₂) until the reaction starts.Then the reaction mixture is diluted to one and half with water, boiledbriefly and filtered in hot. After cooling down it is possible toisolate some of the product D—P(OH)₂. The residue is extracted withCHCl₃ and then recrystallized from glacial acetic acid to give someadditional amount of the product.

Example 76

[0548] D—PCl₂ from D—P(OH)₂

[0549] 0.05 mole of D—P(OH)₂ to 75 mL of PCl₃ within 10 minutes. Afterthe addition, the reaction mixture is stirred for an additional 5minutes. The phosphoric acid produced is separated out and the residueis concentrated under vacuum and distilled to give the product D—PCl₂.Purification can be carried out by sublimating several times to give apure sample for analysis.

Example 77

[0550] D—P(OH)₂ from D—PCl₂

[0551] 0.01 mole of D—PCl₂ is stirred in 50 mL water for about 10 hoursat room temperature. Then the mixture is filtered and the residue isrecrystallized several times from acetonitrile to yield the productD—P(OH)₂.

[0552] Sulfur Containing Derivatives Directly Substituted on the HigherDiamondoids

[0553] Sulfur containing derivatives such as D—SOCl (higher diamondoidylsulfinic acid chloride) are prepared by direct substitution on thehigher diamondoids with SOCl₂ in the presence of AlCl₃ at lowtemperatures. By way of those higher diamondoidyl sulfinic acidchlorides, a variety of sulfur containing derivatives directlysubstituted on the higher diamondoids are prepared. FIG. 20 presentssome representative pathways to derivatize the higher diamondoids viaD—SOCl, D—SH, D—SO₂H, and D—SO₂Cl.

Example 78

[0554] D—SOCl from D

[0555] 40 g (0.3 mole) of AlCl₃ and 200 mL of SOCl₂ are reacted at about−15° C. for about 2 hours with 0.3 mole of a higher diamondoid. Themixture is stirred for an additional 1 hour at this temperature. Thenthe clear solution is allowed to warm to room temperature, and theexcess SOCl₂ is removed under vacuum. The residue is taken up in 300 mLof CCl₄ and carefully decomposed with water. The organic phase isseparated out, washed with water, dried over CaCl₂ and concentrated invacuum. The residue is distilled to give the product D—SOCl.

Example 79

[0556] Higher Diamondoidyl Sulfinic Acid Esters [e.g. D—SO₂CH₃] fromD—SOCl

[0557] 0.1 mole of D—SOCl is heated under reflux for about 6 hours with200 mL of absolute methanol. The solvent is then removed in vacuum andthe residue is distilled to give the product. For further purificationcan be carried out by sublimation under vacuum.

Example 80

[0558] D—SH from D—SO₂CH₃ via Reduction Reaction with LiAlH₄

[0559] 0.1 mole of LiAlH₄ is suspended in 100 mL of absolute ether andheated under reflux for about 1 hour. Then a solution of 0.02 mole ofD—SO₂CH₃ in 100 mL of absolute ether is added dropwise over a period ofabout 2 hours. After about additional 17 hours of stirring under reflux,the excess LiAlH₄ is decomposed with a saturated Na₂SO₄ solution, andthe ether phase is separated out after 100 mL of concentratedhydrochloric acid has been added. The aqueous phase is washed for anadditional two times with ether. The extracts are combined and driedover CaCl₂ and concentrated under vacuum. The residue is sublimated togive D—SH.

Example 81

[0560] D—SO₂H (Higher Diamondoidyl Sulfinic Acid) from D—SOCl

[0561] To 650 mL 5% sodium hydroxide solution is added about 0.25 moleof D—SOCl (crude product) at room temperature. After about 5 hours ofstirring, the temperature is increased to about 50° C., then filtration.Chlorination products remain as residue. The filtrate is acidified withconcentrated hydrochloric acid while cooling with ice, and extractedseveral times with ether. The combined extracts are washed with water,dried over MgSO₄ and concentrated to a dry product. Recrystallizationfrom acetonitrile gives product D—SO₂H.

Example 82

[0562] D—SO₃H (Higher Diamondoidyl Sulfonic Acid) from D—SO₂H (HigherDiamondoidyl Sulfinic Acid) Via Oxidation Reaction with H₂O₂

[0563] 5 mmoles of D—SO₂H is suspended in 25 mL water while adding 1 mL30% hydrogen peroxide. Then the mixture is heated while stirring on awater bath and an additional 3 mL 30% hydrogen peroxide are addeddropwise within 30 minutes. The solution is briefly boiled, filtered andconcentrated under vacuum to dryness at about 30° C. to give the higherdiamondoidyl sulfonic acid monohydrate D—SO₃H H₂O.

Example 83

[0564] D—SC₂H₅ from D—SH

[0565] 0.1 mole of D—SH dissolved in 100 mL ethanol is added whilestirring into a solution of 8 g (0.2 mole) of NaOH in 200 mL water andtreated for about 1 hour at 50° C. with 15.4 g (0.1 mole) ofdiethylsulfate. After an additional 1 hour stirring under reflux, thereaction mixture is cooled down and extracted several times with ether.The combined extracts are concentrated in vacuum and the residue isdistilled over CaCl₂ to give the product D—SC₂H₅.

Example 84

[0566] D—SO₂C₂H₅ from D—SC₂H₅ Via Oxidation Reaction with H₂O₂

[0567] 0.05 mole of D—SC₂H₅ in 100 mL glacial acetic acid is heated toreflux with 17.5 g (0.15 mole) 30% hydrogen peroxide. After about 1 hourof stirring under reflux, the reaction mixture is poured onto ice andfiltered. Recrystallization from ethanol/water gives the productD—SO₂C₂H₅.

Example 85

[0568] D—SO₂H from D—SO₂C₂H₅

[0569] 0.02 mole of D—SO₂C₂H₅and 12 g KOH are heated to 250° C. with 3-5drops of water. Then the temperature is raised to 275° C. in the courseof about 45 minutes, whereby a strong development of a gas takes place.After cooling down, the mixture is dissolved in a little water,acidified with concentrated hydrochloric acid while cooling with ice andextracted several times with ether. The distillation residue from theether extract gives, after recrystallization from acetonitrile, productD—SO₂H.

Example 86

[0570] D—SOCl from D—SO₂H

[0571] 0.05 mole of D—SO₂H is left standing over night with 100 mLfreshly distilled SOCl₂ at room temperature. The excess SOCl₂ is removedunder vacuum, and the residue is distilled, whereby the product D—SOClsolidifies in the receiver.

Example 87

[0572] Higher Diamondoidyl Sulfinic Acid Esters [e.g. D—SO₂C₂H₅] fromD—SOCl

[0573] 0.1 mole of D—SOCl together with 200-300 mL absolute alcohol and7.9 g (0.1 mole) pyridine is heated for 8-12 h under reflux. The excessalcohol is then removed in vacuum and the residue is mixed with ether.The ether solution is washed twice with dilute hydrochloric acid andwater, dried over MgSO₄ and concentrated. The residue is distilled invacuum to give the corresponding ester.

Example 88

[0574] Higher Diamondoidyl Sulfinic Acid Amides [e.g. D—SONH₂ orD—SON(CH₃)₂] from D—SOCl

[0575] 45 mmoles of D—SOCl is heated with 300 mL 25% aqueous ammonia or150 mL 40% aqueous dimethylamine for about 2 hours while stirring underreflux. Then the reaction mixture is concentrated to dryness in vacuumand the residue is extracted with ether. The distillation residue fromthe ether extract is recrystallized from cyclohexane to afford thecorresponding amide.

Example 89

[0576] D—SO₂Cl (Higher Diamondoidyl Sulfonic Acid Chloride) from D—SO₂H

[0577] Into a clear solution of 0.05 mole D—SO₂H and 2 g (0.05 mole)NaOH in 200 mL water is introduced a strong chlorine gas flow atapproximately 5° C. temperature increase within 45 minutes. Afterfiltration, the residue is extracted in ether. The ether solution iswashed chlorine-free with NaHSO₃ solution, dried over MgSO₄ andconcentrated to dryness in vacuum at room temperature. Recrystallizationfrom ethanol gives the product D—SO₂Cl.

Example 90

[0578] D—SH from D—SO₂Cl Via Reduction Reaction with LiAlH₄

[0579] 0.01 mole D—SO₂Cl in 100 mL absolute ether is added dropwisewithin 1 hour to a suspension of 3 g LiAlH₄ in 100 mL absolute ether.After the addition, the reaction mixture is stirred for about 3 hoursunder reflux, then the excess LiAlH₄ is destroyed with dilutehydrochloric acid. The organic phase is separated out, dried over MgSO₄and concentrated. The residue is sublimated several times to give D—SH.

Example 91

[0580] D—SO₂H from D—SO₂Cl

[0581] 10 mmoles D—SO₂Cl and 100 mL 10% sodium hydroxide solution areheated on a water bath for about 4 hours while adding 1 g pyridine.After cooling and filtration, the filtrate is acidified withconcentrated hydrochloric acid and perforated over night with ether. Theether extract is dried over MgSO₄ and concentrated to yield D—SO₂H.

Example 92

[0582] D—Cl from D—SO₂Cl

[0583] 20 mmoles D—SO₂Cl together with 30 mL absolute methanol and 3 gpyridine is heated for about 4 hours at 50° C. while stirring. Then thereaction mixture is poured on ice and extracted with ether. The ethersolution is washed with dilute hydrochloric acid, dried over MgSO₄ andconcentrated. The residue is sublimated to give D—Cl.

Example 93

[0584] D—OH from D—SO₂Cl

[0585] 10 mmoles D—SO₂Cl and 100 mL 25% aqueous ammonia are heated on awater bath for about 3 hours while stirring. The solution isconcentrated in vacuum to dryness, and the residue is sublimated to giveD—OH.

Example 94

[0586] Higher Diamondoidyl Sulfonic Acid Esters and Amides [e.g.D—SO₂OC₂H₅ and D—SO₂N(CH₃)₂] from the Corresponding Sulfinic Acid Estersand Amides [e.g. D—SO₂C₂H₅ and D—SON(CH₃)₂] Via Oxidation Reaction withKMnO₄

[0587] 0.02 mole of the corresponding higher diamondoidyl sulfinic acidester or armide is treated in 150-400 mL acetone at reflux with asaturated solution of KMnO₄ in acetone. After 30 minutes of stirringunder reflux, the reaction mixture is filtered from MnO₂ and the residueis extracted several times with acetone. The combined filtrates are thenconcentrated in vacuum to give the corresponding higher diamondoidylsulfonic acid esters or amides.

Example 95

[0588] Formulations

[0589] The following are representative pharmaceutical formulationscontaining a compound of formula I.

[0590] Tablet Formulation

[0591] The following ingredients are mixed intimately and pressed intosingle scored tablets. Quantity per Ingredient tablet mg compound ofthis invention 400 corn starch 50 croscarmellose sodium 25 lactose 120magnesium stearate 5

[0592] Capsule Formulation

[0593] The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule. Quantity per Ingredient capsule mg compoundof this invention 200 lactose, spray-dried 148 magnesium stearate 2

[0594] Suspension Formulation

[0595] The following ingredients are mixed to form a suspension for oraladministration. Ingredient Amount compound of this invention 1.0 gfumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propylparaben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 gVeegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mgdistilled water q.s. to 100 ml

[0596] Injectable Formulation

[0597] The following ingredients are mixed to form an injectableformulation. Ingredient Amount compound of this invention 0.4 mg sodiumacetate buffer solution 0.4 M 2.0 ml HCl (1N) or NaOH (1N) q.s. tosuitable pH water (distilled, sterile) q.s. to 20 ml

[0598] Testing

[0599] In testing, the MT-2 cell line, a human T-cell leukemia linederived from isolated cord blood lymphocytes cocultured with cells frompatients with adult T-cell leukemia, may be useful. The MT-2 cell linemay be obtained from AIDS Research and Reference Reagent Programme ofthe NIAID, NIH (cat. no. 237, NIH, Bethesda, Md.). The MT-2 cell linecan be successfully used as targets for HIV-1 infection and requiresonly 4 to 5 days for complete cytopathic effect (CPE). (Montefiori etal., J. Clin. Microbiol 1988, 26, 231-235; Pauwels et at., J. Virol.Meth. 1988, 20, 309-321; Harada et al., Science 1985, 229, 563-6)

[0600] The MT-2 cell line may be grown and maintained in RPMI 1640containing 10% fetal calf serum and antibiotics.

[0601] Also in testing, the MN/H9 (HIV-1.sub.MN) (cat. no. 317) virusand VP6 may be used. The MN/H9 may be obtained from the AIDS repository.The AZT resistant strain (AZTR) of HIV-1 (cat. no. 629), which wasisolated from an AIDS patient and developed by Douglas Richman, may alsobe used. The AZT resistant strain of HIV-1 may also obtained from theAIDS repository. (Larder et al., Science, 1989, 243, 1731-1734). VP6 isa primary HIV isolate obtained by culturing PBMC from a patient withfull blown AIDS and kaposi sarcoma with normal phytohemagglutinin (PHA)stimulated PBMC.

[0602] Virus-infected cells may be grown in RPMI 1640 medium,supplemented with 10% fetal bovine serum and 10% interleukin-2.Cell-free supernatant fluid may be collected when the cultures showedpeak infectivity titer and may be used as the virus stock. AZTR and VP6stocks may be grown in MT-2 cells. MN may be grown in H9 cells. The cellfree virus stocks may be prepared as per the standard (HIV ResearchProtocol). The virus stocks may be titrated by tissue culture infectivedose (50%) TCID₅₀ by inoculating tissue culture and determiningobservable effects in 50% of the cultures per Reed and Muench, Amer. J.Hyg., 1938, 27, 493-7.

[0603] Cytotoxicity Assay

[0604] An effective anti-viral drug must be non-toxic to cells. Anyantiviral assays must first confirm the testing candidate is notcytotoxic to the cells used in the assay. Because viruses use cellularmachinery for replication, cytotoxic compounds would inhibit viruses bydefinition. The microliter cytotoxicity assay used may based on theability of living cells to reduce the tetrazolium salt MTT(3[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and form ablue product (Tada, H, et al., J. Immuno. Meth. 1986 93, 157-165;Carmichael et al., Cancer Research 1987, 47, 936). Precisely, when theMT-2 cells are in log phase and 2×10⁴ cells are distributed in each wellalong with separate 100 μl aliquots of diluted compounds to be tested.The test compounds are soluble in ethyl alcohol (EtOH). Ethanol andmedium are incubated in some wells with the cells as an ethanol control.A cell control is also included (wells containing only cells andmedium). The plates are incubated for 5 days at 37° C. in 5% CO₂ andhumidified conditions. Cell viability is determined in each well by theMTT assay. The OD₅₇₀ (optical density at 570 nm) of cells without testcompound is taken as 0% killing and is compared to the OD₅₇₀ of cellswith test compound. The toxicity profile for different compounds is thenscored. In the MTT dye reduction assay, toxicity is indicated as yellowin the wells, with blue color indicating the compound is non-toxic.

[0605] The toxicity of the test compounds is tested at concentrations upto 500 g/mi.

[0606] Anti-HIV Assay

[0607] Stock solutions of different test compounds are appropriatelydiluted to give final concentration of 2.5, 5, 10 and 20 μg/ml in RPMImedium when 100 μl of each dilution is added to three replicate wells in96-well flatbottomed microliter plates. MT-2 cells are inoculated with100 TCID 50 of HIV-1/MN, the AZT resistant isolate or the VP6 isolate inTi-25 flasks and are incubated for two hours at 37° C. The cells arethen washed to remove any remaining free virus, and 2×10⁴ cells aredistributed to each of the wells. In cell control only, uninfected cellsare distributed. Virus control wells have only infected cells andmedium. The plates are incubated at 37° C. for 5 days. HIV-1 inducedsyncytia are observed after 48 hours. Pictures may be taken. After day5, when maximum CPE is observed in virus control wells, the MTT assay isperformed and percent protection is calculated for each test compound byapplying the following formula:$\frac{{({OD\tau}){HIV}} - {({ODc}){HIV}}}{{({ODc}){mock}} - {({ODc}){HIV}}}\quad (\%)$

[0608] in which (OD_(τ))HIV is the optical density measured inHIV-infected cells treated with a given concentration of the testcompound; (OD_(c))HIV is the optical density measured for the controluntreated HIV-infected cells. (OD_(c))mock is the optical densitymeasured for the control untreated mock infected cells. All O.D. valuesare determined at 570 nm. For pretreatment experiments, cells areincubated with test compounds for 1 hour at 37° C. prior to infectionwith the virus. After the adsorption of virus, these cells are washed,the wells replenished with medium containing test compound. Theremaining part of the assay is continued as above. Pictures may be takenon day 5. The percent protection from these tests may be plotted.

[0609] Virus Neutralization Assay

[0610] 50 μl of cell free virus (100 TCID50) are mixed with 50 μl ofdifferent concentrations of test compounds. Virus-compound mixtures areincubated at 37° C. for 1 hour, then are added to the wells of a 96-wellflat-bottomed microtiter plate containing 6×10⁴ MT-2 cells/well. Theplates are incubated at 37° C. in 5% CO₂ humidified atmosphere for 5days. MTT reduction assay is performed on day 5. The neutralizationpattern is assessed.

[0611] While the invention has been described and illustrated herein byreferences to various specific material, procedures and examples, it isunderstood that the invention is not restricted to the particularmaterial combinations of material, and procedures selected for thatpurpose. Numerous variations of such details can be implied as will beappreciated by those skilled in the art.

What is claimed is:
 1. A functionalized higher diamondoid having atleast one functional group and having following Formula I:

wherein D is a higher diamondoid nucleus; and, R¹, R², R³, R⁴, R⁵ and R⁶are each independently selected from a group consisting of hydrogen andcovalently bonded added functional groups; provided that there is atleast one functional group.
 2. The functionalized higher diamondoid ofclaim 1 having one functional group.
 3. The functionalized higherdiamondoid of claim 1 having at least two functional groups.
 4. Thefunctionalized higher diamondoid of claim 3 wherein two functionalgroups are the same.
 5. The functionalized higher diamondoid of claim 3wherein two functional groups are different.
 6. The functionalizedhigher diamondoid of claim 1 wherein the functional groups are selectedfrom the group consisting of halo, thio, oxide, hydroxyl, nitro,sulfonylhalide, sulfonate, phosphine, added alkyl, alkenyl, alkynyl andaryl, with or without substitution.
 7. A functionalized higherdiamondoid of claim 1 which is a higher diamondoid halide wherein atleast one R is halo and the remaining R's are hydrogens.
 8. The higherdiamondoid halide of claim 7 wherein the halo is bromo.
 9. The higherdiamondoid halide of claim 7 wherein the halo is chloro.
 10. The higherdiamondoid halide of claim 7 wherein the halo is iodo.
 11. Thefunctionalized higher diamondoid of claim 1 which is a higher diamondoidhydroxide wherein at least one R is OH and the remaining R's arehydrogens.
 12. The higher diamondoid hydroxide of claim 11 wherein one Ris OH.
 13. The functionalized higher diamondoid of claim 1 which is ahigher diamondoid oxide wherein two R's form an oxide.
 14. Thefunctionalized higher diamondoid of claim 1 which is a higher diamondoidnitrate.
 15. The functionalized higher diamondoid of claim 1, wherein atleast one of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected fromthe group consisting of haloalkyl; haloalkenyl; haloalkynyl;hydroxyalkyl; heteroaryl; and alkylthio.
 16. The functionalized higherdiamondoid of claim 1, wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶is independently selected from a group consisting of alkoxy; aminoalkyl,aminoalkoxy, heterocycloalkoxy, cycloalkyloxy, aryloxy, andheteroaryloxy.
 17. The functionalized higher diamondoid of claim 1,wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is independentlyselected from the group consisting of —C(O)Z wherein Z is hydrogen,alkyl, halo, haloalkyl, halothio, amino, monosubstituted amino,disubstituted amino, cycloalkyl, aryl, heteroaryl; —CO₂Z wherein Z is asdefined previously; —R⁷COZ wherein R⁷ is alkyl, aminoalkyl, or haloalkyland Z is as defined previously; —R⁷COOZ wherein R⁷ and Z are as definedpreviously.
 18. The functionalized higher diamondoid of claim 1, whereinat least one of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected froma group consisting of —NH₂; —NHNH₂; —NHR′, —NR′R″, and —N⁺R′R″R′″wherein R′, R″, and R′″ are independently alkyl, amino, thio, thioalkyl,heteroalkyl, aryl, or heteroaryl; —R⁸NHCOR⁹ wherein R⁸ is selected fromthe group consisting of —CH₂, —OCH₂, —NHCH₂, —CH₂CH₂, and —OCH₂CH₂ andR⁹ is selected from the group consisting of alkyl, aryl, heteroaryl,aralkyl, and heteroaraylkly; and —R¹⁰CONHR¹¹ wherein R¹⁰ is selectedfrom the group consisting of —CH₂, —OCH₂, —NHCH₂, —CH₂CH₂, and —OCH₂CH₂,and R¹¹ is selected from the group consisting of alkyl, aryl,heteroaryl, aralkyl, and heteroaralkyl.
 19. The functionalized higherdiamondoid of claim 1, wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶is independently selected from the group consisting of

wherein: n is 2 or 3; X is oxygen, sulfur, carboxy, or COOZ′ where Z′ ishydrogen or alkyl; Y is oxygen or sulfur; and R¹², R¹³, R¹⁴, and R¹⁵ areindependantly selected from the group consisting of hydrogen, alkyl,heteroalkyl, ary, heteroaryl.
 20. The functionalized higher diamondoidof claim 1, wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently selected from the group consisting of ═N—Z″, wherein Z″ ishydrogen, —NH₂, —OH, alkyl,


21. The functionalized higher diamondoid of claim 1, wherein at leastone of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from thegroup consisting of cyano, cyanoalkyl, cyanoaryl, and cyanoalkylamino.22. The functionalized higher diamondoid of claim 1, wherein at leastone of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from a groupconsisting of —NHR′; —NR′R″; —N⁺R′R″R′″; —NHQ″, aryl; heteroaryl; alkyl;alkenyl; and alkynyl, wherein R′, R″, and R′″ are independently selectedfrom the group consisting of hydrogen; aryl; heteroaryl; alkyl; alkenyl;and alkynyl; or R′ and R″ together with the nitrogen atom form aheterocyclic group with up to 7 ring members; and Q′ is thio, thioalkyl,amino, monosubstituted amino, disubstituted amino, or trisubstitutedamino.
 23. The functionalized higher diamondoid of claim 1, wherein atleast one of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from agroup consisting of —COOR¹⁶ wherein R¹⁶ is alkyl, aryl, or aralkyl;—COR¹⁷ wherein R¹⁷ is alkyl, aryl, heteroalkyl; —NHNH₂; —R₁₈NHCOR¹⁹wherein R¹⁸ is absent, or is selected from the group consisting ofalkylene, arylene, alkarylene, and aryalkylene and R¹⁹ is selected fromthe group consisting of hydrogen, alkyl, —N₂, aryl, amino, and —NHR²⁰wherein R²⁰ is selected from the group consisting of hydrogen,—SO₂-aryl, —SO₂-alkyl, —SO₂-aralkyl, —CONHR²¹ wherein R²¹ is selectedfrom the group consisting of hydrogen, alkyl, and aralkyl, and —CSNHR²¹wherein R²¹ is as defined above; and —COOR²², wherein R²² is alkyl oraryl; and —NR²³—(CH₂)_(n)—NR²⁴R²⁵ wherein R²³, R²⁴, and R²⁵ areindependantly selected from the group consisting of hydrogen, alkyl, andaryl, and n is from 1 to
 20. 24. The functionalized higher diamondoid ofclaim 1, wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently selected from the group consisting of hydrogen; —N═C═N—;—N═C═S; —N═C═O; —R—N═C═O, —R—N═C═S; —N═S═O; —R—N═S═O wherein R is alkyl;—PH₂; —POX₂ wherein X is halo; —PO(OH)₂; —SO₂H; —SOX wherein X is halo;—SO₂R wherein R is alkyl; —SO₂OR; —OSO₃H wherein R is alkyl; —SONR²⁶R²⁷wherein R²⁶ and R²⁷ are independently hydrogen or alkyl; and —N₃;—OC(O)Cl; and —OC(S)Cl.
 25. A functionalized higher diamondoid offormula II D—L—(D)_(n)  II wherein n is 1 or more such as 1 to 10 andespecially 1 to
 4. D is a higher diamondoid nucleus; and L is a linkinggroup selected from the group consisting of —N═C—N—,

wherein R²⁸, R²⁹, R³⁰, R³¹, R³² and R³³ are independently selected fromthe group consisting of hydrogen and alkyl and R³⁴, R³⁵, R³⁶, and R³⁷are independently absent or selected from the group consisting ofhydrogen and alkyl, with the proviso that at least one of R³⁴, R³⁵, R³⁶,and R³⁷ are present, and n and m are independently from 2 to
 20. 26. Thefunctionalized higher diamondoid of formula III R³⁸—D—D—R³⁹  III whereinD is a higher diamondoid nucleus; and R³⁸ and R³⁹ are substituents onthe higher diamondoid nucleus and are independently selected from thegroup consisting of hydrogen; halo; cyano; arylalkoxy; aminoalkyl; and—COOR⁴⁰ wherein R⁴⁰ is hydrogen or alkyl.